Compounds and methods for the treatment of ocular disorders

ABSTRACT

Described herein are compositions and methods for the treatment or prevention of ocular surface disorders including meibomian gland dysfunction, blepharitis, dry eye disease and other inflammatory and/or infectious diseases of the anterior surface of the eye(s). Said compositions and methods comprise keratolytic conjugates which demonstrate keratolytic activity, and anti-inflammatory or other desirable activities. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from ocular surface disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/222,802, filed on Apr. 5, 2021, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE DISCLOSURE

Restasis (0.05% cyclosporine A, Allergan) was approved by the Food andDrug Administration (FDA) to increase tear production in patients whosetear production is presumed to be suppressed due to ocular inflammationassociated with keratoconjunctivitis sicca. Xiidra® (lifitegrastophthalmic solution) 5% is indicated for the treatment of signs andsymptoms of dry eye disease (DED).

SUMMARY OF THE DISCLOSURE

Provided in certain embodiments herein are compounds, pharmaceutical(e.g., ophthalmic) compositions, and methods of treatment. In specificembodiments, methods of treatment provided herein include the treatmentof ocular and/or periocular indications or abnormalities. In someembodiments, the ocular and/or periocular indications or abnormalitiestreated by or with a composition or compound provided herein areindications or abnormalities that have multifactorial etiologies and/orinteractions. In certain embodiments provided herein are compounds (andcompositions comprising such compounds) that have multifunctionalefficacies, such as when administered in or around the eye (e.g., to theocular surface, the eyelid, such as the eyelid margin or the innersurface of the eyelid, or the like).

In some embodiments, provided herein is a method of treatinginflammation or hyperkeratosis (e.g., of the eye or skin).

In certain embodiments, methods provided herein involve the method oftreating meibomian gland dysfunction (MGD).

Currently there are no approved pharmacological agents useful for thetreatment of MGD. The recognition that terminal duct obstruction fromhyperkeratinization of the ductal epithelium on meibomian glands is acore mechanism behind meibomian gland dysfunction (MGD) is consistentwith clinical experience demonstrating that effective treatments for MGDrequire resolution of ductal obstruction and evacuation of glandularcontents (Nichols et al, 2011; Lane et al, 2012; Blackie et al, 2015).Warm compresses and thermal/mechanical devises (e.g., LipiFlow) are usedin an attempt to raise the internal temperature of the meibomian glandsover the normal melting point for meibum (i.e., 32° C. to 40° C.) in anattempt to resolve terminal duct obstruction (Lane et al, 2012).Unfortunately, warm compresses are unable to achieve this benefit forseverely obstructed glands which can having a melting point >40° C.Current technology for removing keratinized obstruction of the meibomiangland also includes physical removal methods (e.g., debridement andgland probing), which are quite painful to patients.

Subsequent to a period of MGD, various stages of inflammatory orbacterial disease at the ocular surface are frequently observed becausemeibomian gland obstruction can cause a cascade of events that includefurther deterioration of the glands (Knop, IOVS, 2011) from stasis ofthe meibum in the secretory glands, mechanical pressure and stress fromglandular obstruction, and increased bacterial growth that is associatedwith the downstream release of bacterial lipases, toxic mediators,and/or inflammatory mediators. All these factors reduce the qualityand/or quantity of meibum the glands can release which in turn can causechronic mechanical traumatization of the conjunctival, corneal andeyelid tissues which will lead to further tissue damage and the releaseof inflammatory mediators. Thus, many patients suffering from MGD alsohave inflammatory disease affecting their conjunctiva, cornea, larcrimalgland, lids or goblet cells causing comorbid conditions such as dry eyesyndrome or blepharitis for which there is an unmet medical need.

For example, literature has used the terms posterior blepharitis and MGDas if they were synonymous, but these terms are not interchangeable.Posterior blepharitis describes inflammatory conditions of the posteriorlid margin, of which MGD can be one possible cause. In its earlieststages, MGD may not be associated with clinical signs characteristic ofposterior blepharitis. At this stage, affected individuals may besymptomatic, but alternatively, they may be asymptomatic and thecondition regarded as subclinical. As MGD progresses, symptoms developand lid margin signs, such as changes in meibum expressibility andquality and lid margin redness, may become more visible. At this point,an MGD-related posterior blepharitis is said to be present.

In certain embodiments, provided herein are methods of treating ocular(or dermatological) disorders associated with keratosis (e.g., lidkeratosis, surface ocular keratosis, and/or gland blockage—such as inMGD), microbial infiltration/infection (e.g., bacterialinfiltration/infection), and/or inflammation (such as inflammationassociated keratosis or not associated with keratosis). In certaininstances, disorders of the skin and/or eye (and/or surroundtissue/skin) are difficult to differentially diagnose and/or havemultiple etiologies. For example, in some instances, it can be difficultto distinguish between ocular disorders that involve (1) inflammationonly, (2) inflammation associated with keratolytic activity, (3)inflammation associated with both keratolytic activity (e.g., inducingkeratosis) and microbial infiltration, (4) keratolytic activity, but notinflammation and/or microbial infiltration, or various othercombinations. In some instances, compounds and compositions providedherein can be used in such ocular and/or dermatological indicationswithout the need for differential diagnosis (which can be difficult,e.g., because of similar symptom scores, etc.). Further, many ocularand/or dermatological disorders involve multiple etiologies, suchinflammation, microbial infiltration, keratolytic activity, or variouscombinations thereof. As a result, therapeutic agents, such as thosedescribed herein, that target multiple etiologies are beneficial inproviding therapeutic efficacy, such as by targeting both an underlyingcondition (e.g., keratolytic activity and/or microbial infiltration) anda symptom, such as inflammation or dry eye.

As such, provided herein are compounds, compositions, methods, andformulations for the treatment of ocular (e.g., periocular) ordermatological disorders, such as those having abnormalities havingmultifactorial etiologies. In specific embodiments, ocular disordersinclude, by way of non-limiting example, surface disorders, such as MGD,dry eye and associated inflammatory and bacterial disease.

Provided in some embodiments herein is a compound, or a pharmaceuticallyacceptable salt or solvate thereof, having the structure of Formula (I):

In some embodiments, each R^(Q) is independently H, R^(N), substitutedor unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,wherein at least one R^(Q) is R^(N). In some embodiments, R^(N) isD-L^(a)-. In some embodiments, D is a keratolytic agent. In someembodiments, L^(a) is a linker.

In some embodiments, each R^(Q) is independently H, R^(N), substitutedor unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,wherein one R^(Q) is R^(N). In some embodiments, each R^(Q) isindependently H, R^(N), substituted alkyl, or unsubstituted alkyl. Inspecific embodiments, at least one R^(Q) is R^(N). In some embodiments,each R^(Q) is independently H, R^(N), or unsubstituted alkyl, whereinone R^(Q) is R^(N). In some embodiments, the unsubstituted alkyl ismethyl, ethyl, or propyl. In some embodiments, each R^(Q) isindependently H, R^(N), or unsubstituted heteroalkyl, wherein one R^(Q)is R^(N). In some embodiments, each R^(Q) is independently H, methyl, orR^(N), wherein one R^(Q) is R^(N).

In some embodiments, alkyl is optionally substituted with one or moreselected from the group consisting of —OH, —SH, substituted orunsubstituted alkyl (alkylene), unsubstituted or substituted aryl,substituted or unsubstituted heteroalkyl, —NHCOMe, —O(C═O)CH₂OH,—O(C═O)CH(CH₃)OH, —O(C═O)alkyl, and —(C═O)Oalkyl (e.g., where alkyl ismethyl, ethyl, propyl, isopropyl, or t-butyl). In some embodiments, thealkyl is substituted with one or more selected from the group consistingof alkyl, heterocycloalkyl, —NHCOMe, —O(C═O)alkyl, and —(C═O)Oalkyl(e.g., where alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl).

In some embodiments, the heterocycloalkyl is dithiolane oxide.

In some embodiments, provided herein is a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I-A):

In some embodiments, R′ is D-L^(a)-. In some embodiments, D is akeratolytic agent. In some embodiments, L^(a) is a linker.

In some embodiments, L^(a) comprises one or more linker groups, eachlinker group being selected from the group consisting of a bond, —O—,—S—, halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide,ester, and carbonyl (>C═O). In some embodiments, each linker group isselected from the group consisting of a bond, —O—, —S—, halo, alkyl(alkylenyl), heteroalkyl (heteroalkylenyl), and ester. In someembodiments, L^(a) comprises one or more linker groups, each linkergroup being selected from the group consisting of a bond, alkyl(alkylenyl), heteroalkyl (heteroalkylenyl), ester, and carbonyl (>C═O).In some embodiments, each linker group is selected from the groupconsisting of a bond, halo, alkyl (alkylenyl), heteroalkyl(heteroalkylenyl), and ester. In some embodiments, each linker group isselected from alkyl (alkylene) and heteroalkyl (heteroalkylene), thealkyl (alkylene) or heteroalkyl (heteroalkylene) being optionallysubstituted.

In some embodiments, L^(a) is alkyl (alkylene) substituted with oxo andone or more of alkyl and heteroalkyl. In some embodiments, the alkyl orheteroalkyl is substituted with one or more halo, alkyl, or haloalkyl.In some embodiments, the alkyl or heteroalkyl is substituted with one ormore alkyl or haloalkyl. In some embodiments, L^(a) comprises one ormore linker group, each linker group being independently selected from abond, —O—, —S—, halo, (C═O), —(C═O)alkyl-, —(C═O)heteroalkyl-, —(C═O)O—,—(C═O)Oalkyl-, —(C═O)Oheteroalkyl-, —(C═O)S—, —(C═O)Salkyl-,—(C═O)Sheteroalkyl-, alkylene, or heteroalkylene, where each alkyl,heteroalkyl, alkylene, or heteroalkyl is independently optionallysubstituted. In some embodiments, L^(a) comprises (C═O), —(C═O)alkyl-,—(C═O)heteroalkyl-, —(C═O)O—, —(C═O)Oalkyl-, —(C═O)Oheteroalkyl-,—(C═O)OalkylO—, —(C═O)OheteroalkylO—, —(C═O)S—, —(C═O)Salkyl-,—(C═O)Sheteroalkyl-, alkylene, and heteroalkylene. In some embodiments,L^(a) comprises one or more linker group, each linker group beingindependently selected from a bond, (C═O), —(C═O)alkyl-,—(C═O)heteroalkyl-, —(C═O)O—, —(C═O)Oalkyl-, —(C═O)Oheteroalkyl-,—(C═O)S—, —(C═O)Salkyl-, —(C═O)Sheteroalkyl-, alkylene, orheteroalkylene, where each alkyl, heteroalkyl, alkylene, or heteroalkylis independently optionally substituted. In some embodiments, L^(a)comprises (C═O), —(C═O)alkyl-, —(C═O)heteroalkyl-, —(C═O)O—,—(C═O)Oalkyl-, —(C═O)Oheteroalkyl-, —(C═O)OalkylO—,—(C═O)OheteroalkylO—, —(C═O)S—, —(C═O)Salkyl-, —(C═O)Sheteroalkyl-,alkylene, and heteroalkylene. In some embodiments, 1′ comprises —O—,(C═O), —(C═O)alkyl-, —(C═O)O—, —(C═O)Oalkyl-, and/or —(C═O)OalkylO—. Insome embodiments, L′ is a bond.

In some embodiments, the linker comprises the structure of Formula (A):

wherein:

-   -   Q is a bond, —O—, —S—, or optionally substituted amino;    -   each G¹ and G² is independently hydrogen, halo, alkyl,        heteroalkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is        optionally substituted; and    -   g is 1-20.

In some embodiments, the compound comprises more than one linker ofFormula (A). In some embodiments, Q is a bond or —O—. In someembodiments, Q is a bond and each G¹ and G² is independently hydrogen,alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl are eachoptionally substituted. In some embodiments, Q is —O— and each G¹ and G²is independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl orcycloalkyl are optionally substituted. In some embodiments, Q is a bondor —O— and each G¹ is hydrogen and each G² is independently alkyl orhaloalkyl. In some embodiments, Q is a bond or —O— and each G¹ ishydrogen and each G² is methyl. In some embodiments, Q is a bond or —O—and each G¹ and G² is hydrogen. In some embodiments, Q is a bond andeach G¹ is hydrogen and each G² is methyl. In some embodiments, Q is abond and each G¹ and G² is hydrogen. In some embodiments, Q is —O—, eachG¹ is hydrogen, and each G² is methyl. In some embodiments, Q is —O— andeach G¹ and G² is hydrogen.

In some embodiments, g is 1-20. In some embodiments, g is 1-10. In someembodiments, g is 1-5. In some embodiments, g is 2. In some embodiments,g is 1.

In some embodiments, g is 1 or 2, Q is a bond and each G¹ is hydrogen,and each G² is methyl. In some embodiments, g is 1 or 2, Q is a bond,and each G¹ and G² is hydrogen. In some embodiments, g is 1 or 2, Q is—O—, each G¹ is hydrogen, and each G² is methyl. In some embodiments, gis 1 or 2, Q is —O—, and each G¹ and G² is hydrogen.

In some embodiments, the linker comprises one or more bond, oxo, —O—,methylene,

In some embodiments, g is 1-20. In some embodiments, g is 1-10. In someembodiments, g is 1-8. In some embodiments, g is 1, 2, 3, 4, 5, 6, 7, or8.

In some embodiments, the linker comprises one or more of:

In some embodiments, the linker comprises one or more —O—, oxo,methylene,

In some embodiments, the linker comprises one or more oxo, one or more—O—, and:

In some embodiments, the linker comprises one or more oxo, one or more—O—, and:

In some embodiments, L is a bond.

In some embodiments, any linker or L provided herein is attached to therest of a molecule provided herein to form a ketal. In some embodiments,any linker or L provided herein is attached to the rest of a moleculeprovided herein to form an ester.

In some embodiments, D comprises a radical of one or more keratolyticgroup (e.g., each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Up), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, D comprises a radical of one or more keratolyticgroup, each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Up), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc).

In some embodiments, D comprises a thiol radical of one or morekeratolytic group, each thiol radical of the one or more keratolyticgroup being independently selected from the group consisting of a thiolradical of thioglycolic acid (TGA), a thiol radical of thiolactic acid(TLac), a thiol radical of dihydrolipoic acid (diHLip), a thiol radicalof N-acetyl cysteine (NAC), a thiol radical of cysteine (Cys), a thiolradical of glutathione (GSH), a thiol radical of captopril (Cap), and athiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHLip-Lipox]•.

In some embodiments, D is substituted (e.g., straight or branched)alkyl, substituted (e.g., straight or branched) heteroalkyl, orsubstituted heterocycloalkyl (e.g., (N−) substituted with alkyl furthersubstituted with oxo and thiol). In some embodiments, the substitutedalkyl is substituted with one or more (alkyl) substituent, at least one(alkyl) substituent being independently selected from the groupconsisting of —SH, substituted unsaturated cycloalkyl (e.g., beingsubstituted with one or more C₁-C₄ alkyl), and substituted orunsubstituted disulfide containing heterocycloalkyl (e.g., dithiolaneoxide). In some embodiments, the substituted alkyl being substitutedwith one or more (alkyl) substituent, at least one (alkyl) substituentbeing independently selected from the group consisting of —SH,substituted unsaturated cycloalkyl (e.g., being substituted with one ormore C₁-C₄ alkyl), and dithiolanyl oxide. In some embodiments, thesubstituted heteroalkyl being substituted with one or more (heteroalkyl)substituent, at least one (heteroalkyl) substituent being independentlyselected from the group consisting of —SH, —COOH, and thioalkyl. In someembodiments, the substituted alkyl, substituted heteroalkyl, orsubstituted heterocycloalkyl are further optionally substituted.

In some embodiments, D is substituted (e.g., straight or branched)alkyl, substituted (e.g., straight or branched) heteroalkyl, orsubstituted heterocycloalkyl (e.g., (N−) substituted with alkyl furthersubstituted with oxo and thiol). In some embodiments, the substitutedalkyl being substituted with one or more (alkyl) substituent, at leastone (alkyl) substituent being independently selected from the groupconsisting of —SH and dithiolanyl oxide. In some embodiments, thesubstituted heteroalkyl being substituted with one or more (heteroalkyl)substituent, at least one (heteroalkyl) substituent being independentlyselected from the group consisting of —SH, —COOH, and thioalkyl. In someembodiments, the substituted alkyl, substituted heteroalkyl, orsubstituted heterocycloalkyl are further optionally substituted.

In some embodiments, D is substituted (e.g., straight or branched)alkyl, the (e.g., straight or branched) alkyl being substituted with oneor more substituent, each substituent being independently selected fromthe group consisting of thiol, amino, acetamide, substituted unsaturatedcycloalkyl (e.g., being substituted with one or more C₁-C₄ alkyl), andsubstituted heterocycloalkyl (e.g., dithiolanyl oxide).

In some embodiments, D is substituted alkyl, the alkyl being substitutedwith substituted heterocycloalkyl (e.g., dithiolanyl oxide). In someembodiments, the substituted heterocycloalkyl is substituted with one ormore substituent, each substituent being independently selected from thegroup consisting of C₁-C₃ alkyl, oxo (e.g., or —O—), and —COOH.

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D-L^(a)- is:

In some embodiments, D-L^(a)- is:

In some embodiments, D is substituted heterocycloalkyl (e.g.,N-substituted with alkyl further substituted with oxo and thiol).

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D-L^(a)- is:

In some embodiments, D is substituted (e.g., linear or branched)heteroalkyl comprising one or more ester, one or more amide, and/or oneor more disulfide (e.g., within the (e.g., linear or branched)heteroalkyl chain).

In some embodiments, D is substituted (e.g., linear or branched)heteroalkyl comprising one ester (e.g., within the (e.g., linear orbranched) heteroalkyl chain).

In some embodiments, D is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two amide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, D is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two disulfide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, D is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one disulfide (e.g., within the (e.g.,linear or branched) heteroalkyl chain).

In some embodiments, D is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one or two disulfide and one amide(e.g., within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, D is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with one or more substituent, each substituent beingindependently selected from the group consisting of thioalkyl, amino,carboxylic acid, C₁-C₆ alkyl, acetamide, thiol, oxo, and optionallysubstituted (e.g., N-attached) heterocycloalkyl (e.g., optionallysubstituted with carboxylic acid).

In some embodiments, D is substituted branched heteroalkyl.

In some embodiments, D comprises:

In some embodiments, D is:

In some embodiments, D comprises:

In some embodiments, D is:

In some embodiments, D is:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D is:

In some embodiments, D comprises:

In some embodiments, D is:

In some embodiments, D comprises:

In some embodiments, D is:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises:

In some embodiments, D comprises: HOCH₂—, HOCH(CH₃)—, HO(CH₂CH₂O)₄CH₂—,HO(CH₂CH₂O)₄CH₂CH₂—, HOCH₂(C═O)—, HOCH(CH₃)(C═O)—,HO(CH₂CH₂O)₄CH₂(C═O)—, HO(CH₂CH₂O)₄CH₂CH₂(C═O)—, CH₃O(C═O)—,CH₃CH₂O(C═O)—, (CH₃)₂CO(C═O)—, (CH₃)₃CO(C═O)—, CH₃(C═O)—, CH₃CH₂(C═O)—,(CH₃)₂C(C═O)—, (CH₃)₃C(C═O)—, HOCH₂(C═O)—, HO(CH₃)CH(C═O)—,HO(CH₃)CH(C═O)O(CH₃)CH(C═O)—, CH₃(C═O)O(CH₃)CH(C═O)—,CH₃O(C═O)O(CH₃)CH(C═O)—, CH₃O(C═O)(CH₃)CHO(C═O)—,CH₃CH₂O(C═O)(CH₃)CHO(C═O)—, HOCH₂(HOCH₂)CHCH₂O(C═O)—,CH₃(C═O)OCH₂(CH₃(C═O)OCH₂)CHCH₂O(C═O)—,(CH₃)₃C(C═O)OCH₂((CH₃)₃C(C═O)OCH₂)CHCH₂O(C═O)—,HO(CH₃)CH(C═O)OCH₂(HO(CH₃)CH(C═O)OCH₂)CHCH₂O(C═O)—, HSCH₂(C═O)—,HS(CH₃)CH(C═O)—, HSCH₂(NH₂)CH(C═O)—, HSCH₂(CH₃(C═O)NH)CH(C═O)—,HOOC(NH₂)CHCH₂CH₂(C═O)NH(HSCH₂)CH(C═O)NHCH₂(C═O)—,—(C═O)CH(NH₂)CH₂CH₂(C═O)NHCH(CH₂SH)(C═O)NHCH₂COOH,HS(CH₃)₂C(C═O)NH(SHCH₂)CH(C═O)—, HOOC(NH₂)CHCH₂SSCH₂CH(NH₂)(C═O)—,HSCH₂(CH₃(C═O)NH)CH(C═O)OCH(CH₃)(C═O)—,

In some embodiments, D comprises: HSCH₂(C═O)—, HS(CH₃)CH(C═O)—,HSCH₂(NH₂)CH(C═O)—, HSCH₂(CH₃(C═O)NH)CH(C═O)—,HOOC(NH₂)CHCH₂CH₂(C═O)NH(HSCH₂)CH(C═O)NHCH₂(C═O)—,—(C═O)CH(NH₂)CH₂CH₂(C═O)NHCH(CH₂SH)(C═O)NHCH₂COOH,HS(CH₃)₂C(C═O)NH(SHCH₂)CH(C═O)—, HOOC(NH₂)CHCH₂SSCH₂CH(NH₂)(C═O)—,HSCH₂(CH₃(C═O)NH)CH(C═O)OCH(CH₃)(C═O)—,

In some embodiments, D-L^(a) is:

In some embodiment, D-L^(a) is

In some embodiments, D is a “keratolytic agent” radical that, uponrelease, hydrolysis, or other mechanism metabolizes or otherwiseproduces (e.g., when administered to an individual or patient, such asin or around the eye, such as the eyelid margin) an active keratolyticagent (e.g., a carboxylic acid and/or a thiol). In some instances, uponrelease (e.g., by hydrolysis or other mechanism), D produces a pluralityof active keratolytic agents. In some instances, the active keratolyticagent comprises one or more of —SH, —OH, COOH (or COO—), or disulfide.In some embodiments, the active keratolytic agent is a carboxylic acid.In some embodiments, the active keratolytic agent is selected from thegroup consisting of acetic acid, glycolic acid, lactic acid, lipoicacid, pivalic acid, isobutryic acid, butyric acid, propionic acid,formic acid, and carbonic acid. In some embodiments, the activekeratolytic agent is a thiol. In some embodiments, the activekeratolytic agent is a carboxylic acid.

In some embodiments, one or more group of the keratolytic agent (e.g.,thiol, hydroxy, carboxylic acid, amide, or amine) is protected or masked(e.g., with optionally substituted C₁-C₆ alkyl (e.g., being optionallysubstituted with oxo)). In some embodiments, one or more thiol of thekeratolytic agent is protected or masked with acetyl. In someembodiments, one or more amine of the keratolytic agent is protected ormasked with acetyl. In some embodiments, one or more carboxylic acid ofthe keratolytic agent is protected or masked with methyl, ethyl, propyl,isopropyl, or t-butyl. In some embodiments, one or more carboxylic acidof the keratolytic agent is protected or masked with ethyl.

In some embodiments, L^(a) is attached to D by a bond.

In some embodiments, any L or linker provided herein comprises one ormore substituted or unsubstituted alkoxy (e.g., polyethylene glycol(PEG)).

In some embodiments, any L or linker provided herein comprises acompound having a structure of Formula (B):

—X(C═O)—.

In some embodiments, X is a bond or O. In some embodiments, X is a bond.In some embodiments, X is O.

In some embodiments, any L or linker provided herein is attached to thecompound having a structure of Formula (B). In some embodiments, thelinker is —(C═O)(OCR⁸R⁹)—.

In some embodiments, the linker is —(C═O)OCH(CH₃)—. In some embodiments,the linker is —(C═O)(OCH₂CH₂)_(z) and attached to the compound having astructure of Formula (B).

In some embodiments, z is an integer from 1-20. In some embodiments, zis an integer from 1-10.

In some embodiments, z is an integer from 1-5. In some embodiments, z is1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, z is 4. In someembodiments, z is 8.

In some embodiments, the linker is —(C═O)(OCH₂CH₂)₂ and attached to—O(C═O)—. In some embodiments, the linker is —(C═O)(OCH₂CH₂)₄ andattached to —O(C═O)—. In some embodiments, the linker is—(C═O)(OCH₂CH₂)₈ and attached to —O(C═O)—.

In some embodiments, the compound having the structure of Formula (B) isattached to a keratolytic agent provided herein (e.g., as describedelsewhere herein). In some embodiments, the compound having thestructure of Formula (B) is attached to and includes at least a portionof a keratolytic agent provided herein (e.g., as described elsewhereherein).

In some embodiments, the compound having the structure of Formula (B) isattached to any R or R′ provided herein (e.g., as described elsewhereherein).

In certain instances, provided herein is a combination of ananti-inflammatory and/or anti-microbial moiety (e.g., having a structureof any formula provided herein, minus the R′) with a keratolytic moiety(e.g., being represented by and/or having a structure of D). In certainembodiments, such moieties are radicals connected by a linker that is abond, with the keratolytic moiety being hydrolyzable to produce both (1)an anti-inflammatory and/or anti-microbial agent and (2) one or moreactive keratolytic agent. In some embodiments, such moieties areradicals connected by a hydrolyzable linker, with the hydrolyzablelinker being hydrolyzable, such that both (1) an anti-inflammatoryand/or anti-microbial agent and (2) one or more active keratolytic agentare released (e.g., in vivo, such as after therapeutic (e.g., topical)delivery to the eye and/or skin).

In some embodiments, a compound provided herein comprises a firstradical (e.g., a first radical of Formula I (or any other formulaprovided herein)) that is dimerized with a second radical (e.g., asecond radical of Formula I (or any other formula provided herein)). Insome embodiments, each radical of Formula I (or any other formulaprovided herein) is dimerized through an —SH group thereof (e.g.,forming an S—S linkage).

In some embodiments, provided herein is a compound, or apharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)thereof, having the structure of Formula (Ia):

In some embodiments, L is bond, —(C═O)(OCR⁸R⁹)—, or—(C═O)(OCR⁸R⁹)_(z)O—. In some embodiments, L is bond, —(C═O)O(CR⁸R⁹)—,or —(C═O)O(CR⁸R⁹)_(z)O—. In some embodiments, each R⁸ and R⁹ isindependently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or R⁸ and R⁹ are taken together with the atoms towhich they are attached to form a C₃-C₅-cycloalkyl. In some embodiments,z is 1-6. In some embodiments, X is absent or —O—. In some embodiments,R is substituted (e.g., straight or branched) alkyl, substituted (e.g.,straight or branched) heteroalkyl, or substituted heterocycloalkyl(e.g., (N−) substituted with alkyl further substituted with oxo andthiol). In some embodiments, the substituted alkyl is substituted withone or more (alkyl) substituent, at least one (alkyl) substituent beingindependently selected from the group consisting of —SH, substituted orunsubstituted (e.g., unsaturated) cycloalkyl, and substitutedheteroalkyl (e.g., dithiolanyl oxide). In some embodiments, thesubstituted alkyl is substituted with one or more (alkyl) substituent,at least one (alkyl) substituent being independently selected from thegroup consisting of —SH, substituted or unsubstituted (e.g.,unsaturated) cycloalkyl, and dithiolanyl oxide. In some embodiments, thesubstituted alkyl is substituted with one or more (alkyl) substituent,at least one (alkyl) substituent being independently selected from thegroup consisting of —SH and dithiolanyl oxide. In some embodiments, thesubstituted heteroalkyl is substituted with one or more (heteroalkyl)substituent, at least one (heteroalkyl) substituent being independentlyselected from the group consisting of —SH, —COOH, and thioalkyl. In someembodiments, the substituted alkyl, substituted heteroalkyl, orsubstituted heterocycloalkyl are further optionally substituted.

In some embodiments, L is bond. In some embodiments, L is—(C═O)(OCR⁸R⁹)— or —(C═O)(OCR⁸R⁹)_(z)O—. In some embodiments, L is—(C═O)(OCR⁸R⁹)—. In some embodiments, L is —(C═O)(OCR⁸R⁹)_(z)O—. In someembodiments z is 1-3. In some embodiments, z is 1. In some embodiments,each R⁸ and R⁹ is independently H or C₁-C₃-alkyl. In some embodiments,each R⁸ is H and each R⁹ is C₁-C₃-alkyl. In some embodiments, each R⁸ isH and each R⁹ is CH₃. In some embodiments, R⁸ and R⁹ are H. In someembodiments, L is —(C═O)OCH(CH₃)—. In some embodiments, L is—(C═O)OCH(CH₃)O—.

In some embodiments, X is absent. In some embodiments, X is —O—.

In some embodiments, L is —(C═O)OCH(CH₃)— or —(C═O) OCH(CH₃)O— and X isabsent or —O—.

In some embodiments, L is —(C═O)OCH(CH₃)— and X is absent. In someembodiments, L is —(C═O)OCH(CH₃)O— and X is absent.

In some embodiments, L is —(C═O)OCH(CH₃)— and X is —O—. In someembodiments, L is —(C═O)OCH(CH₃)O— and X is —O—.

In some embodiments, L is bond and X is absent.

In some embodiments, R is substituted alkyl, substituted heteroalkyl, orsubstituted heterocycloalkyl.

In some embodiments, R is substituted (e.g., straight or branched)alkyl, the (e.g., straight or branched) alkyl being substituted with oneor more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of thiol, amino,acetamide, substituted unsaturated cycloalkyl (e.g., being substitutedwith one or more C₁-C₄ alkyl), and substituted heterocycloalkyl (e.g.,dithiolanyl oxide). In some embodiments, R is substituted (e.g.,straight or branched) alkyl, the (e.g., straight or branched) alkylbeing substituted with thiol. In some embodiments, R is substituted(e.g., straight or branched) alkyl, the (e.g., straight or branched)alkyl being substituted with thiol and amide. In some embodiments, R issubstituted (e.g., straight or branched) alkyl, the (e.g., straight orbranched) alkyl being substituted with thiol and acetamide (e.g.,—N(C═O)CH₃). In some embodiments, R is substituted (e.g., straight orbranched) alkyl, the (e.g., straight or branched) alkyl beingsubstituted with 1,2-dithiolanyl oxide. In some embodiments, R issubstituted (e.g., straight or branched) alkyl, the (e.g., straight orbranched) alkyl being substituted with substituted unsaturatedcycloalkyl (e.g., being substituted with one or more C₁-C₄ alkyl).

In some embodiments, R is substituted alkyl. In some embodiments, R issubstituted alkyl, wherein the substituted alkyl is substituted with oneor more alkyl substituent, at least one alkyl substituent beingindependently selected from the group consisting of substituted orunsubstituted cycloalkyl and substituted heterocycloalkyl. In someembodiments, R is substituted alkyl, the alkyl being substituted withsubstituted heterocycloalkyl. In some embodiments, R is substitutedalkyl, the alkyl being substituted with 1,2-dithiolanyl oxide. In someembodiments, R is substituted alkyl, the alkyl being substituted withsubstituted heterocycloalkyl (e.g., C₅-C₁₅ heterocycloalkyl (e.g., C₁₂heterocycloalkyl with one or more disulfide and one or more amide withinthe heterocycloalkyl ring)) being substituted with one or moresubstituent, at least one substituent being independently selected fromthe group consisting of C₁-C₃ alkyl, oxo, and —COOH. In someembodiments, the substituted alkyl is further optionally substituted.

In some embodiments, L is bond, X is absent, and R is substituted (e.g.,straight or branched) alkyl, the (e.g., straight or branched) alkylbeing substituted with one or more (alkyl) substituent, each (alkyl)substituent being independently selected from the group consisting ofthiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., beingsubstituted with one or more C₁-C₄ alkyl), and substitutedheterocycloalkyl (e.g., dithiolanyl oxide).

In some embodiments, L is bond, X is absent, and R is substituted alkyl,wherein the substituted alkyl is substituted with one or more alkylsubstituent, at least one alkyl substituent being independently selectedfrom the group consisting of substituted or unsubstituted cycloalkyl andsubstituted heterocycloalkyl. In some embodiments, the substituted alkylis further optionally substituted.

In some embodiments, R is:

wherein:

-   -   each R^(4a) and R^(4b) is independently H, halogen, or        substituted or unsubstituted alkyl;    -   p is an integer from 1-10; and    -   q is an integer from 1-3.

In some embodiments, q is 1 and p is an integer from 3-5.

In some embodiments, each R^(4a) and R^(4b) is H.

In some embodiments, R is:

wherein:

-   -   R⁵ is —SR^(1c);        -   R^(1c) is:            -   substituted alkyl or substituted heteroalkyl,                -   wherein the alkyl is substituted with one or more                    alkyl substituent, each alkyl substituent being                    independently selected from the group consisting of                    carboxylic acid, —SH, thioalkyl, acetamide, amino,                    oxo, and optionally substituted heterocycloalkyl,                    and the heteroalkyl is substituted with one or more                    heteroalkyl substituent, each heteroalkyl                    substituent being independently selected from the                    group consisting of oxo, carboxylic acid, amino,                    thioalkyl, thiol, acetamide, and C₁-C₃ alkyl;    -   R⁶ and R⁷ are each independently H, substituted or unsubstituted        alkyl, or substituted or unsubstituted heteroalkyl;    -   each R¹⁰ and R¹¹ is independently H, halogen, C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or two of R¹⁰        and R¹¹ are taken together with the atoms to which they are        attached to form a C₃-C₅-cycloalkyl; and    -   s is an integer from 1-10.

In some embodiments, R⁶, R⁷, R¹⁰ and R¹¹ are each H, and s is 1-3.

In some embodiments, R^(1c) is heteroalkyl substituted with carboxylicacid. In some embodiments, R^(1c) is alkyl substituted with one or morealkyl substituent, each alkyl substituent being independently selectedfrom the group consisting of carboxylic acid and acetamide.

In some embodiments, R⁵ is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl comprising one or more ester, one or more amide, and/or oneor more disulfide (e.g., within the (e.g., linear or branched)heteroalkyl chain).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl comprising one ester (e.g., within the (e.g., linear orbranched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two amide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two disulfide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one disulfide (e.g., within the (e.g.,linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one or two disulfide and one amide(e.g., within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of thioalkyl, amino, carboxylic acid, C₁-C₆ alkyl, thiol,oxo, and optionally substituted (e.g., N-attached) heterocycloalkyl(e.g., optionally substituted with carboxylic acid). In someembodiments, R is substituted linear heteroalkyl, the linear heteroalkylbeing substituted with thioalkyl, amino, and carboxylic acid. In someembodiments, R is substituted linear heteroalkyl, the linear heteroalkylbeing substituted with thioalkyl, thiol, and C₁-C₄ alkyl.

In some embodiments, R is substituted branched heteroalkyl, the branchedheteroalkyl being substituted with one or more carboxylic acid. In someembodiments, R is substituted branched heteroalkyl, the branchedheteroalkyl being substituted with one or more C₁-C₄ alkyl, one or moreoxo, and one or more N-attached pyrrolidine substituted with carboxylicacid. In some embodiments, R is substituted linear heteroalkyl, thelinear heteroalkyl being substituted with amino and carboxylic acid. Insome embodiments, R is substituted linear heteroalkyl, the linearheteroalkyl being substituted with thioalkyl.

In some embodiments, R is substituted linear heteroalkyl, the linearheteroalkyl being substituted with acetamide and carboxylic acid.

In some embodiments, R is substituted heteroalkyl, wherein thesubstituted heteroalkyl is substituted with one or more heteroalkylsubstituent, each heteroalkyl substituent being independently selectedfrom the group consisting of —COOH, substituted heterocycloalkyl,acetamide, alkoxy, oxo, thiol, C₁-C₃ alkyl, and thioalkyl. In someembodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with —COOH, —CH₂SH, and/or optionally substituted N-attachedheterocycloalkyl. In some embodiments, the substituted heteroalkyl isfurther optionally substituted. In some embodiments, the substitutedheteroalkyl is further substituted with one or more other substituent,each substituent being independently selected from the group consistingof acetamide, amino, C₁-C₆ alkyl, thiol, and oxo.

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with one or more substituent, each substituent beingindependently selected from the group consisting of —COOH and acetamide.

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with one or more substituent, each substituent beingindependently selected from the group consisting of oxo and acetamide(e.g., wherein the heteroalkyl chain comprises a disulfide bond and—O—).

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with one or more substituent, each substituent beingindependently selected from the group consisting of C₁-C₃ alkyl, oxo,and substituted N-attached heterocycloalkyl (e.g., optionallysubstituted with —COOH).

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with one or more substituent, each substituent beingindependently selected from the group consisting of C₁-C₃ alkyl, oxo,—COOH, and thiol (e.g., wherein the branched heteroalkyl chain comprisestwo disulfide bonds and two —NH—).

In some embodiments, R is substituted heteroalkyl comprising one or moreester, amide, or disulfide bond within the heteroalkyl chain.

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with —COOH, —CH₂SH, and/or optionally substituted N-attachedheterocycloalkyl, and being further substituted with one or more othersubstituent, each substituent being independently selected from thegroup consisting of acetamide, amino, C₁-C₆ alkyl, thiol, and oxo.

In some embodiments, R is substituted heteroalkyl comprising twodisulfide bonds within the heteroalkyl chain, the heteroalkyl beingsubstituted with —COOH or substituted N-attached heterocycloalkyl. Insome embodiments, the heteroalkyl is further substituted with one ormore other substituent, each substituent being independently selectedfrom the group consisting of acetamide and C₁-C₆ alkyl.

In some embodiments, R is substituted heteroalkyl comprising onedisulfide bond within the heteroalkyl chain, the heteroalkyl beingsubstituted with acetamide, —COOH, and —SH.

In some embodiments, R is heterocycloalkyl N-substituted with alkyl, thealkyl being further substituted with oxo and/or thiol.

In some embodiments, L is bond, X is absent, and R is substituted (e.g.,linear or branched) heteroalkyl, the (e.g., linear or branched)heteroalkyl being substituted with one or more (heteroalkyl)substituent, each (heteroalkyl) substituent being independently selectedfrom the group consisting of thioalkyl, amino, carboxylic acid, C₁-C₆alkyl, acetamide, thiol, oxo, and optionally substituted (e.g.,N-attached) heterocycloalkyl (e.g., optionally substituted withcarboxylic acid).

In some embodiments, L is bond, X is absent, and R is substitutedheteroalkyl, wherein the substituted heteroalkyl is substituted with oneor more heteroalkyl substituent, at least one heteroalkyl substituentbeing independently selected from the group consisting of —COOH,substituted heterocycloalkyl, and thioalkyl. In some embodiments, thesubstituted heteroalkyl is further optionally substituted.

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is substituted branched heteroalkyl.

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R—X-L is:

In some embodiments, R—X-L is:

In some embodiments, R—X-L is:

-   -   In some embodiments, R is substituted heterocycloalkyl (e.g.,        N-substituted with alkyl further substituted with oxo and/or        thiol).

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R—X-L is

In some embodiments, R comprises a radical of one or more keratolyticgroup (e.g., each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Lip), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R comprises a radical of one or more keratolyticgroup, each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Lip), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc).

In some embodiments, R comprises a thiol radical of one or morekeratolytic group, each thiol radical of the one or more keratolyticgroup being independently selected from the group consisting of a thiolradical of thioglycolic acid (TGA), a thiol radical of thiolactic acid(TLac), a thiol radical of dihydrolipoic acid (diHLip), a thiol radicalof N-acetyl cysteine (NAC), a thiol radical of cysteine (Cys), a thiolradical of glutathione (GSH), a thiol radical of captopril (Cap), and athiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•, [diHLip-Cap-Cap]•,[diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•, [diHLip-Lipox-Lipox]•,and [diHLip-Lipox]•.

In some embodiments, R is:

In some embodiments, R—X-L- is:

In some embodiments, R—X-L- is:

In some embodiments, the compound is other than a compound having thestructure:

Provided in some embodiments herein is a compound, or a pharmaceuticallyacceptable salt or solvate (e.g., or a stereoisomer) thereof, having thestructure of Formula (Ib):

In some embodiments, L is bond, —(C═O)(OCR⁸R⁹)₂—, or—(C═O)(OCR⁸R⁹)_(z)O—. In some embodiments, each R⁸ and R⁹ isindependently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or R⁸ and R⁹ are taken together with the atoms towhich they are attached to form a C₃-C₅-cycloalkyl. In some embodiments,z is 1-6. In some embodiments, X is absent or —O—.

In some embodiments, R^(x) is:

In some embodiments, R^(1a) and R^(1b) are each independently —H or—SR^(1c). In some embodiments, each R^(1c) is independently substitutedor unsubstituted (e.g., straight or branched) alkyl (e.g., substitutedwith one or more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of carboxylic acid,—SH, thioalkyl, acetamide, amino, oxo, optionally substitutedheterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with —COOH))or substituted or unsubstituted (e.g., straight or branched) heteroalkyl(e.g., substituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, andC₁-C₃ alkyl). In some embodiments, each R^(2a), R^(2b), R^(2c), R^(2d),R^(2e), and R^(2f) is independently H, halogen, C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or two of R^(2a) andR^(2b), R^(2c) and R^(2d), or R^(2e) and R^(2f) are taken together withthe atoms to which they are attached to form a C₃-C₅-cycloalkyl. In someembodiments, m is an integer from 1-10. In some embodiments, n and o areeach independently an integer from 0-3. In some embodiments, n and o areeach independently an integer from 1-3.

In some embodiments, L, R⁸, R⁹, X, and z are each described elsewhereherein.

In some embodiments, n and o are each independently 0, 1, or 2. In someembodiments, n is 1 or 1. In some embodiments, n is 2. In someembodiments, o is 0 or 1. In some embodiments, o is 0. In someembodiments, o is 0 and n is 2.

In some embodiments, n and o are each independently 0 or 1. In someembodiments, n is 0 or 1.

In some embodiments, n is 1. In some embodiments, o is 0 or 1. In someembodiments, o is 0. In some embodiments, o is 0 and n is 1.

In some embodiments, m is 3-5. In some embodiments, m is 4. In someembodiments, o is 0 and m is 4. In some embodiments, n is 2 and m is 4.In some embodiments, o is 0, n is 2, and m is 4.

In some embodiments, m is 3-5. In some embodiments, m is 4. In someembodiments, n is 0 and m is 4. In some embodiments, n is 1 and m is 4.In some embodiments, o is 0, n is 1, and m is 4.

In some embodiments, each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), andR^(2f) is independently H, halogen, C₁-C₃alkyl, or C₁-C₃haloalkyl. Insome embodiments, each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), andR^(2f) is independently H, halogen, C₁-C₃alkyl, or C₁-C₃haloalkyl, atleast one of R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) beinghalogen, C₁-C₃alkyl, or C₁-C₃haloalkyl. In some embodiments, eachR^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) is H.

In some embodiments, R^(x) is:

In some embodiments, R^(x) is:

In some embodiments, R^(1a) and R^(1b) are each independently —H or—SR^(1c). In some embodiments, each R^(1c) is independently substitutedor unsubstituted (e.g., straight or branched) alkyl (e.g., substitutedwith one or more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of carboxylic acid,—SH, thioalkyl, acetamide, amino, oxo, optionally substitutedheterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with —COOH))or substituted or unsubstituted (e.g., straight or branched) heteroalkyl(e.g., substituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, andC₁-C₃ alkyl).

In some embodiments, R^(1a) is —H or —SR^(1c) and R^(1b) is —SR^(1c), orR^(1b) is —SR^(1c) and R^(1b) is —H or —SR^(1c). In some embodiments,R^(1a) is —H or —SR^(1c) and R^(1b) is —SR^(1c). In some embodiments,R^(1a) is —H and R^(1b) is —SR^(1c). In some embodiments, R^(1a) is—SR^(1c) and R^(1b) is —H or —SR^(1c). In some embodiments, R^(1a) is—SR^(1c) and R^(1b) is —SR^(1c). In some embodiments, R^(1a) and R^(1b)are each —SR^(1c).

In some embodiments, R^(1a) and R^(1b) each independently comprise aradical of one or more keratolytic group (e.g., each radical of the oneor more keratolytic group being independently selected from the groupconsisting of a radical of glycolic acid (GA), a radical of thioglycolicacid (TGA), a radical of lactic acid (Lac), a radical of thiolactic acid(TLac), a radical of lipoic acid (Lip), a radical of lipoic acidsulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radicalof N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical ofglutathione (GSH), a radical of captopril (Cap), and a radical ofbucillamine (Buc)).

In some embodiments, R^(1a) and R^(1b) are each independently a radicalof one or more keratolytic group, each radical of the one or morekeratolytic group being independently selected from the group consistingof a radical of glycolic acid (GA), a radical of thioglycolic acid(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid(TLac), a radical of lipoic acid (Lip), a radical of lipoic acidsulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radicalof N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical ofglutathione (GSH), a radical of captopril (Cap), and a radical ofbucillamine (Buc).

In some embodiments, R^(1a) and R^(1b) each independently comprise a(thiol) radical of one or more keratolytic group, each (thiol) radicalof the one or more keratolytic group being independently selected fromthe group consisting of a (thiol) radical of thioglycolic acid (TGA), a(thiol) radical of thiolactic acid (TLac), a (thiol) radical ofdihydrolipoic acid (diHLip), a (thiol) radical of N-acetyl cysteine(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical ofglutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol)radical of bucillamine (Buc).

In some embodiments, R^(1a) and R^(1b) are each independently a thiolradical of one or more keratolytic group, each thiol radical of the oneor more keratolytic group being independently selected from the groupconsisting of a thiol radical of thioglycolic acid (TGA), a thiolradical of thiolactic acid (TLac), a thiol radical of dihydrolipoic acid(diHLip), a thiol radical of N-acetyl cysteine (NAC), a thiol radical ofcysteine (Cys), a thiol radical of glutathione (GSH), a thiol radical ofcaptopril (Cap), and a thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHLip-Lipox]•.

In some embodiments, the thiol radical of the keratolytic group is thepoint of attachment of R^(1a) and/or R^(1b) to the rest of the molecule.In some embodiments, (the thiol radical of) R^(1a) and/or R^(1b) eachindependently attach to the rest of the molecule to form a disulfidebond.

In some embodiments, R^(1a) and R^(1b) are each independently —H or:

In some embodiments, R^(1a) and R^(1b) are the same. In someembodiments, R^(1a) and R^(1b) are each —SR^(1c) and the same. In someembodiments, R^(1a) and R^(1b) are different. In some embodiments,R^(1a) and R^(1b) are each SR^(1c) and different.

In some embodiments, L is bond, X is absent, and R^(x) is:

In some embodiments, L is —(C═O)OCH(CH₃)—, X is absent, and R^(x) is:

In some embodiments, L is —(C═O)OCH(CH₃)—, X is absent, and R^(x) is:

In some embodiments, each R^(1c) is independently substituted orunsubstituted (e.g., straight or branched) alkyl or substituted orunsubstituted (e.g., straight or branched) heteroalkyl. In someembodiments, each R^(1c) is independently substituted (e.g., straight orbranched) alkyl or substituted (e.g., straight or branched) heteroalkyl.In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) alkyl. In some embodiments, each R^(1c) is (thesame) substituted (e.g., straight or branched) alkyl. In someembodiments, each R^(1c) is (a different) substituted (e.g., straight orbranched) alkyl.

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) heteroalkyl. In some embodiments, each R^(1c) is(the same) substituted (e.g., straight or branched) heteroalkyl. In someembodiments, each R^(1c) is (a different) substituted (e.g., straight orbranched) heteroalkyl.

In some embodiments, one of R^(1c) is substituted (e.g., straight orbranched) alkyl and the other is substituted (e.g., straight orbranched) heteroalkyl.

In some embodiments, each R^(1c) is the same. In some embodiments, eachR^(1c) is different.

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) alkyl, the substituted alkyl being substitutedwith one or more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of carboxylic acid,—SH, thioalkyl (e.g., —CH₂SH), acetamide (e.g., —NH(C═O)CH₃), amino,oxo, and optionally substituted heterocycloalkyl (e.g., N-attachedpyrrolidinyl substituted with —COOH).

In some embodiments, the optionally substituted heterocycloalkyl is:

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) heteroalkyl, the substituted heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of carboxylic acid, amino, thioalkyl (e.g., —CH₂SH), thiol,acetamide (e.g., —NH(C═O)CH₃), and C₁-C₃ alkyl.

In some embodiments, R^(1c) is:

In some embodiments, R^(1a), R^(1b), and each R^(1c) each independentlycomprise one or more substituent that is a carboxylic acid or an ester.In some embodiments, R^(1a), R^(1b), and each R^(1c) each independentlycomprise one or more substituent that is a carboxylic acid (e.g.,—(C═O)OH). In some embodiments, R^(1a) comprises one or more substituentthat is a carboxylic acid (e.g., —(C═O)OH). In some embodiments, R^(1b)comprises one or more substituent that is a carboxylic acid (e.g.,—(C═O)OH). In some embodiments, each R^(1c) independently comprises oneor more substituent that is a carboxylic acid (e.g., —(C═O)OH). In someembodiments, R^(1a), R^(1b), and each R^(1c) each independently compriseone or more substituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl). Insome embodiments, R^(1a) comprises one or more substituent that is anester (e.g., —(C═O)O—C₁-C₄alkyl). In some embodiments, R^(1b) comprisesone or more substituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl). Insome embodiments, each R^(1c) independently comprises one or moresubstituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl).

In some embodiments, the —(C═O)OH of R^(1a), R^(1b), and/or R^(1c) isoptionally esterified (e.g., —(C═O)OH or —(C═O)O—C₁-C₄alkyl). In someembodiments, the C₁-C₄alkyl is methyl, ethyl, propyl, isopropyl, butyl,or t-butyl.

Provided in some embodiments herein is a compound, or a pharmaceuticallyacceptable salt or solvate (e.g., or a stereoisomer) thereof, having thestructure of Formula (Ic):

In some embodiments, L is bond, —(C═O)(OCR¹R⁹)_(z)—, or—(C═O)(OCR⁸R⁹)₂O—. In some embodiments, each R⁸ and R⁹ is independentlyH, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or R⁸ and R⁹ are taken together with the atoms towhich they are attached to form a C₃-C₅-cycloalkyl. In some embodiments,z is 1-6. In some embodiments, X is absent or —O—.

In some embodiments, R^(y) is:

In some embodiments, each R^(4a) and R^(4b) is independently H, halogen,or substituted or unsubstituted alkyl. In some embodiments, p is aninteger from 1-10. In some embodiments, q is an integer from 1-3.

In some embodiments, L, R⁸, R⁹, z, and X are each described elsewhereherein.

In some embodiments, R^(y) is:

In some embodiments, each R^(4a) and R^(4b) is independently H, halogen,or substituted or unsubstituted alkyl. In some embodiments, p is aninteger from 1-10. In some embodiments, q is an integer from 1-3.

In some embodiments, q is 1 or 2. In some embodiments, q is 1. In someembodiments, p is an integer from 3-5. In some embodiments, p is 4. Insome embodiments, q is 1 and p is 4.

In some embodiments, each R^(4a) and R^(4b) is independently H orsubstituted or unsubstituted alkyl.

In some embodiments, each R⁴¹ and R^(4b) is independently H, halogen,C₁-C₃alkyl, or C₁-C₃haloalkyl. In some embodiments, each R^(4a) andR^(4b) is H.

In some embodiments, q is 1, p is an integer from 3-5, and each R^(4a)and R^(4b) is independently H, halogen, C₁-C₃alkyl, or C₁-C₃haloalkyl.In some embodiments, q is 1, p is 4, and each R^(4a) and R^(4b) is H.

In some embodiments, L is —(C═O)OCH(CH₃)—, X is absent, and R^(y) is:

In some embodiments, provided herein is a compound, or apharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)thereof, having the structure of Formula (Id):

In some embodiments, L is bond, —(C═O)(OCR⁸R⁹)_(z)—, or—(C═O)(OCR⁸R⁹)₂O—. In some embodiments, each R⁸ and R⁹ is independentlyH, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or R⁸ and R⁹ are taken together with the atoms towhich they are attached to form a C₃-C₅-cycloalkyl. In some embodiments,z is 1-6. In some embodiments, X is absent or —O—.

In some embodiments, R² is:

In some embodiments, R⁵ is —SR^(1c). In some embodiments, R^(1c) issubstituted or unsubstituted (e.g., straight or branched) alkyl (e.g.,substituted with one or more (alkyl) substituent, each (alkyl)substituent being independently selected from the group consisting ofcarboxylic acid, —SH, thioalkyl, acetamide, amino, oxo, optionallysubstituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substitutedwith —COOH)) or substituted or unsubstituted (e.g., straight orbranched) heteroalkyl (e.g., substituted with one or more (heteroalkyl)substituent, each (heteroalkyl) substituent being independently selectedfrom the group consisting of carboxylic acid, amino, thioalkyl, thiol,acetamide, and C₁-C₃ alkyl). In some embodiments, R⁶ and R⁷ are eachindependently H, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl. In some embodiments, each R¹⁰ and R¹¹ isindependently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or two of R¹⁰ and R¹¹ are taken together with theatoms to which they are attached to form a C₃-C₅-cycloalkyl. In someembodiments, s is an integer from 1-10.

In some embodiments, L, R⁸, R⁹, X, and z are each described elsewhereherein.

In some embodiments, R⁵ is —SR^(1c). In some embodiments, Ru issubstituted or unsubstituted (e.g., straight or branched) alkyl (e.g.,substituted with one or more (alkyl) substituent, each (alkyl)substituent being independently selected from the group consisting ofcarboxylic acid, —SH, thioalkyl, acetamide, amino, oxo, optionallysubstituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substitutedwith —COOH)) or substituted or unsubstituted (e.g., straight orbranched) heteroalkyl (e.g., substituted with one or more (heteroalkyl)substituent, each (heteroalkyl) substituent being independently selectedfrom the group consisting of carboxylic acid, amino, thioalkyl, thiol,acetamide, and C₁-C₃ alkyl). In some embodiments, R⁶ and R⁷ are eachindependently H, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl. In some embodiments, each R¹⁰ and R¹¹ isindependently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or two or more of R¹⁰ and R¹¹ are taken together withthe atoms to which they are attached to form a C₃-C₅-cycloalkyl. In someembodiments, s is an integer from 1-10.

In some embodiments R^(1c) is substituted alkyl or substitutedheteroalkyl.

In some embodiments R^(1c) is substituted alkyl, the alkyl beingsubstituted with one or more alkyl substituent, each alkyl substituentbeing independently selected from the group consisting of carboxylicacid, —SH, thioalkyl, acetamide, amino, oxo, and optionally substitutedheterocycloalkyl. In some embodiments, R^(1c) is alkyl substituted withone or more alkyl substituent, each alkyl substituent beingindependently selected from the group consisting of carboxylic acid andacetamide.

In some embodiments R^(1c) is substituted heteroalkyl, the heteroalkylbeing substituted with one or more heteroalkyl substituent, eachheteroalkyl substituent being independently selected from the groupconsisting of oxo, carboxylic acid, amino, thioalkyl, thiol, acetamide,and C₁-C₃ alkyl. In some embodiments, R^(1c) is heteroalkyl substitutedwith carboxylic acid.

In some embodiments, R^(1c) is substituted heteroalkyl, the heteroalkylbeing substituted with —COOH and oxo. In some embodiments, R^(1c) issubstituted heteroalkyl, the heteroalkyl being substituted with oxo andacetamide. In some embodiments, R^(1c) is substituted heteroalkyl, theheteroalkyl being substituted with C₁-C₃ alkyl, oxo, and substitutedN-attached heterocycloalkyl. In some embodiments, R^(1c) is substitutedheteroalkyl, the heteroalkyl being substituted with —COOH, C₁-C₃ alkyl,oxo, and thiol.

In some embodiments, R⁶ and R⁷ are each independently H or substitutedor unsubstituted alkyl (e.g., C₁-C₃ alkyl optionally substituted withoxo). In some embodiments, R⁶ and R⁷ are each independently H or C₁-C₃alkyl optionally substituted with oxo. In some embodiments, R¹ and R⁷are each independently H or —(C═O)CH₃. In some embodiments, R⁶ is H andR⁷ is H or —(C═O)CH₃. In some embodiments, R⁶ is H and R⁷ is —(C═O)CH₃.In some embodiments, R⁶ and R⁷ are H.

In some embodiments, each R¹⁰ and R¹¹ is independently H, halogen,C₁-C₃alkyl, or C₁-C₃haloalkyl.

In some embodiments, each R¹⁰ and R¹¹ is H.

In some embodiments, s is 1-3. In some embodiments, s is 1. In someembodiments, s is 1 and R¹⁰ and R¹¹ are H.

In some embodiments, R⁶, R⁷, R¹⁰ and R¹¹ are each H, and s is 1-3.

In some embodiments, R⁵ comprises a radical of one or more keratolyticgroup (e.g., each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Lip), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R⁵ is a radical of one or more keratolytic group,each radical of the one or more keratolytic group being independentlyselected from the group consisting of a radical of glycolic acid (GA), aradical of thioglycolic acid (TGA), a radical of lactic acid (Lac), aradical of thiolactic acid (TLac), a radical of lipoic acid (Lip), aradical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoicacid (diHLip), a radical of N-acetyl cysteine (NAC), a radical ofcysteine (Cys), a radical of glutathione (GSH), a radical of captopril(Cap), and a radical of bucillamine (Buc).

In some embodiments, R⁵ comprises a (thiol) radical of one or morekeratolytic group, each (thiol) radical of the one or more keratolyticgroup being independently selected from the group consisting of a(thiol) radical of thioglycolic acid (TGA), a (thiol) radical ofthiolactic acid (TLac), a (thiol) radical of dihydrolipoic acid(diHLip), a (thiol) radical of N-acetyl cysteine (NAC), a (thiol)radical of cysteine (Cys), a (thiol) radical of glutathione (GSH), a(thiol) radical of captopril (Cap), and a (thiol) radical of bucillamine(Buc).

In some embodiments R⁵ is a thiol radical of one or more keratolyticgroup, each thiol radical of the one or more keratolytic group beingindependently selected from the group consisting of a thiol radical ofthioglycolic acid (TGA), a thiol radical of thiolactic acid (TLac), athiol radical of dihydrolipoic acid (diHLip), a thiol radical ofN-acetyl cysteine (NAC), a thiol radical of cysteine (Cys), a thiolradical of glutathione (GSH), a thiol radical of captopril (Cap), and athiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHUp-NAC-NAC]•, [diHUp-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHUp-Lipox]•.

In some embodiments, the thiol radical of the keratolytic group is thepoint of attachment of R⁵ to the rest of the molecule. In someembodiments, R⁵ attaches to the rest of the molecule to form a disulfidebond.

In some embodiments, R⁵ is:

In some embodiments, R⁵ comprises one or more substituent that is acarboxylic acid or an ester. In some embodiments, R⁵ comprises one ormore substituent that is a carboxylic acid (e.g., —(C═O)OH). In someembodiments, R⁵ comprises one or more substituent that is an ester(e.g., —(C═O)O—C₁-C₄alkyl).

In some embodiments, the —(C═O)OH of R⁵ is optionally esterified (e.g.,—(C═O)OH or —(C═O)O—C₁-C₄alkyl). In some embodiments, the C₁-C₄alkyl ismethyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

In some embodiments, R^(z) is:

In some embodiments, R⁷ is H or —(C═O)CH₃. In some embodiments, R⁷ is H.In some embodiments, R⁷ is —(C═O)CH₃.

In some embodiments, R^(1c) is described elsewhere herein.

In some embodiments, provided herein is a pharmaceutical compositioncomprising any compound provided herein, such as a compound representedby any one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ib),Formula (Ic), Formula (Id), Table 1, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient. Insome embodiments, the pharmaceutical composition is suitable forophthalmic administration. In some embodiments, the pharmaceuticalcomposition is suitable for topical ophthalmic administration. In someembodiments, topical ophthalmic administration is administration inand/or around the eye, such as to the eyelid margin.

In some embodiments, topical ophthalmic administration is administrationto the ocular surface and the inner surface to the eyelid.

In some embodiments, a compound or a pharmaceutical compositioncomprising any compound provided herein, such as a compound of any oneof Formula (I), Formula (I-A), Formula (Ia), Formula (Ib), Formula (Ic),Formula (Id), Table 1, or a pharmaceutically acceptable salt thereof, issubstantially hydrolytically stable (e.g., stable in an aqueouscomposition (e.g., solution), such as a buffer solution orophthalmically acceptable aqueous composition). In some embodiments, thecompound or the pharmaceutical composition is formulated in an aqueousvehicle. In some embodiments, the compound or the pharmaceuticalcomposition is formulated and stored in an aqueous vehicle. In someinstances, compositions or formulations provided herein are chemicallyand/or physically stable in an aqueous composition.

In some embodiments, a compound provided herein, such as a compound ofany one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ib),Formula (Ic), Formula (Id), Table 1, or a pharmaceutically acceptablesalt thereof, is reduced to one or more keratolytic agent (e.g., a freeform of a radical of Formula (I), Formula (I-A), Formula (Ia), Formula(Ib), Formula (Ic), Formula (Id), or Table 1, such as wherein R is anegative charge or H) and/or hydrolyzed to an active pharmaceuticalagent (e.g., a free form of a radical of Formula (I), Formula (I-A),Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1, suchas wherein R is a negative charge or H). In some embodiments, thecompound or pharmaceutical composition is reduced to one or morekeratolytic agent in an ocular space. In some embodiments, the compoundor pharmaceutical composition is reduced to one or more keratolyticagent by a reductase in an ocular space.

In some embodiments, a compound provided herein, such as a compound ofany one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ib),Formula (Ic), Formula (Id), Table 1, or a pharmaceutically acceptablesalt thereof, is hydrolyzed to an active pharmaceutical agent (e.g., afree form of a radical of Formula (I), Formula (I-A), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), or Table 1, such as wherein Ris a negative charge or H) and a keratolytic agent. In some embodiments,the compound or pharmaceutical composition is hydrolyzed to an activepharmaceutical agent and a keratolytic agent in an ocular space. In someembodiments, the compound or pharmaceutical composition is hydrolyzed toan active pharmaceutical agent and a keratolytic agent by an esterase inan ocular space. In some embodiments, the active pharmaceutical agent isan anti-bacterial agent. In some embodiments the anti-bacterial agent isazithromycin. In some embodiments, the keratolytic agent is a carboxylicacid. In some embodiments, the carboxylic acid is selected from thegroup consisting of acetic acid, glycolic acid, lactic acid, lipoicacid, pivalic acid, isobutryic acid, butyric acid, propionic acid,formic acid, and carbonic acid. In some embodiments, the activekeratolytic agent is a thiol.

In some embodiments, a compound or a pharmaceutical compositioncomprising any compound provided herein, such as a compound of any oneof Formula (I), Formula (I-A), Formula (Ia), Formula (Ib), Formula (Ic),Formula (Id), Table 1, or a pharmaceutically acceptable salt thereof. Incertain embodiments, the composition further comprises an amount of afree form of a radical of any of Formula (I), Formula (I-A), Formula(Ia), Formula (Ib), Formula (Ic), Formula (Id), Table 1, or the like(such as wherein the free form is the radical, wherein R is a negativecharge or an H). In some embodiments, a composition provided hereincomprises a (e.g., weight or molar) ratio of a compound provided hereinto a free form of a radical of Formula (I), Formula (I-A), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), Table 1, or a pharmaceuticallyacceptable salt thereof (e.g., wherein R is a negative charge or an H)is about 1:99 to about 100:0 (e.g., the amount of the free form of theradical relative to the overall amount of free form of the radical plusthe conjugate is between 0% (weight or molar) and 99%). In someembodiments, the relative amount of the free form of the radical is 0%to about 50%, such 0% to about 20%, 0% to about 10%, about 0.1% to about10%, about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%,or the like (percentages being weight/weight or mole/mole percentages).In some instances, such aqueous compositions are pre-manufactured or aremanufactured at the time of application in order to maintain highconcentrations of the compound relative to the free form of a radicalthereof. In some embodiments, such concentrations of the compound arepresent in the composition for at least 45 minutes in an aqueouscomposition (such as in an aqueous composition, e.g., a HEPES buffer,such as under the conditions described herein, such as in Table 2).Table 2 of the Examples illustrate good stability of the compositionsprovided herein and such recitations are incorporated in the disclosurehereof. Further, in some instances, compounds provided herein releasefree form of a radical of a compound of Formula (I), Formula (I-A),Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1,(e.g., wherein R is a negative charge or H), such as when administeredto an individual (e.g., ocular (e.g., peri-ocular) or dermatologicaladministration). In more specific instances, when administered to anindividual at a location with esterases and/or reductases present, rapidrelease of active (free) forms of a radical of Formula (I), Formula(I-A), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table1, (e.g., wherein R is a negative charge or H) (and, a keratolytic agentand/or agent that further produces active keratolytic agent(s) (e.g., byfurther hydrolysis and/or reduction thereof)).

In some embodiments, provided herein a compound or a pharmaceuticalcomposition comprising any compound provided herein, such as a compoundof any one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ib),Formula (Ic), Formula (Id), Table 1, or a pharmaceutically acceptablesalt thereof, has keratolytic effects (e.g., reduces disulfide (S—S)bonds) (e.g., in any environment provided herein).

Provided in some embodiments herein is a method of treating inflammationand/or hyperkeratosis, the method comprising administering to anindividual (e.g., in need thereof) any compound provided herein (e.g.,of any Formula or Table provided herein) (e.g., in a therapeuticallyeffective amount). In specific embodiments, the inflammation and/orhyperkeratosis is inflammation and/or hyperkeratosis of the eye,periocular structures (e.g., eyelid), and/or skin.

Provided in some embodiments herein is a method of treating a dermal oran ocular disease or disorder in an individual, comprising administeringto the individual in need thereof a composition comprising any compoundprovided herein, such as a compound represented by any one of Formula(I), Formula (I-A), Formula (Ia), Formula (Ib), Formula (Ic), Formula(Id), Table 1, or a pharmaceutically acceptable salt thereof. In someembodiments, the dermal or the ocular disease or disorder is associatedwith keratosis, microbial infiltration, microbial infection,inflammation, or any combination thereof.

Provided in some embodiments herein is a method of treating adermatological or an ophthalmic disease or disorder in an individual inneed of thereof, comprising administering to the individual in needthereof a composition comprising any compound provided herein, such as acompound represented by any one of Formula (I), Formula (I-A), Formula(Ia), Formula (Ib), Formula (Ic), Formula (Id), Table 1, or apharmaceutically acceptable salt thereof. In some embodiments, thedermatological or ophthalmic disease or disorder is inflammation orhyperkeratosis of the eyes or skin (e.g., the ocular surface). In someembodiments, the dermatological or ophthalmic dermatological disease ordisorder is selected from the group consisting of meibomian glanddysfunction (MGD), dry eye disease (DED), ocular manifestations of graftversus host disease, vernal keratoconjunctivitis, atopickeratoconjunctivitis, Cornelia de Lange Syndrome, evaporative eyedisease, aqueous deficiency dry eye, blepharitis, and seborrheicblepharitis.

In some embodiments, the dermatological or ophthalmic disease ordisorder is inflammation or hyperkeratosis (e.g., of the eyes or skin),such as, for example, meibomian gland dysfunction (MGD), dry eye disease(DED), ocular manifestations of graft versus host disease, vernalkeratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de LangeSyndrome, evaporative eye disease, aqueous deficiency dry eye,blepharitis, seborrheic blepharitis, or any combination thereof.

In some embodiments, the ophthalmic disease or disorder is selected fromdry eye, lid wiper epitheliopathy (LWE), contact lens discomfort (CLD),contact lens discomfort, dry eye syndrome, evaporative dry eye syndrome,aqueous deficiency dry eye syndrome, blepharitis, keratitis, meibomiangland dysfunction, conjunctivitis, lacrimal gland disorder, inflammationof the anterior surface of the eye, infection of the anterior surface ofthe eye, infection of the lid, demodex lid infestation, lid wiperepitheliopathy and autoimmune disorder of the anterior surface of theeye.

In some embodiments, provided herein is a method of treating an ocular(e.g., peri-ocular) or dermatological indication (e.g., associated withkeratolytic activity, inflammation, and/or microbial infiltration), themethod comprising administering a therapeutically effective amount of acompound or composition provided herein. In some embodiments, acomposition provided herein (e.g., used in a method provided herein)comprises a compound provided herein in a therapeutically effectiveamount (e.g., at a concentration effective to treatkeratosis/keratolytic activity, inflammation, and/or microbialinfiltration), in the eye, surrounding tissue, or skin. In someembodiments, a (e.g., pharmaceutical and/or ophthalmic) compositionprovided herein comprises about 0.1 wt. % to about 10 wt. % of acompound provided herein.

In some embodiments, ocular and/or dermatological disorders include, forexample, inflammatory conditions of the eyelids (e.g., hordeolum (stye),blepharitis, and chalazion), ocular surface (e.g., dry eye disease andanterior uveitis) and posterior eye (e.g., posterior and pan-uveitis),abnormalities of the peri-ocular glands (e.g., meibomian glanddysfunction (MGD)), allergic-type conditions, (e.g., eczema, atopicdermatitis, atopic keratoconjunctivitis refractory to topical steroidtreatment, and vernal keratoconjunctivitis), surgical complications(e.g., corneal transplant rejection, post-corneal transplant glaucoma,cataracts secondary to phakic corneal transplant, fungal infections inkeratoplasty patients, and post-LASIK dry eye and/or poor refractiveoutcomes), corneal abnormalities (e.g., inflammatory corneal ulceration,rheumatoid corneal ulcers, and Thygeson's superficial punctatekeratitis), conjunctival abnormalities (e.g., iridocyclitis, ligneousconjunctivitis), ocular complications from systemic treatments and/orautoimmune diseases (e.g., pauciarticular juvenile rheumatoid arthritis,graft versus host disease, and sjogren's syndrome) and/or infectiousdisease of the anterior surface of the eye. In some embodiments,provided herein are compositions and methods for the treatment of ocularand periocular abnormalities that have multifactorial etiologies andinteractions.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurpose identified herein.

DETAILED DESCRIPTION Certain Definitions

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof, and so forth. When ranges are used herein forphysical properties, such as molecular weight, or chemical properties,such as chemical formulae, all combinations and subcombinations ofranges and specific embodiments therein are intended to be included. Theterm “about” when referring to a number or a numerical range means thatthe number or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range may vary between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that in other certain embodiments, for example,an embodiment of any composition of matter, composition, method, orprocess, or the like, described herein, may “consist of” or “consistessentially of” the described features.

The terms “treat,” “treating,” or “treatment” as used herein, includereducing, alleviating, abating, ameliorating, relieving, or lesseningthe symptoms associated with a disease, disease state, or indication(e.g., addiction, such as opioid addiction, or pain) in either a chronicor acute therapeutic scenario. Also, treatment of a disease or diseasestate described herein includes the disclosure of use of such compoundor composition for the treatment of such disease, disease state, orindication.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O radical.

“Alkyl” generally refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, such as havingfrom one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). Unless otherwisestate, alkyl is saturated or unsaturated (e.g., an alkenyl, whichcomprises at least one carbon-carbon double bond). Disclosures providedherein of an “alkyl” are intended to include independent recitations ofa saturated “alkyl,” unless otherwise stated. Alkyl groups describedherein are generally monovalent, but may also be divalent (which mayalso be described herein as “alkylene” or “alkylenyl” groups). Incertain embodiments, an alkyl comprises one to thirteen carbon atoms(e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one toeight carbon atoms (e.g., C₁-C₈ alkyl). In other embodiments, an alkylcomprises one to five carbon atoms (e.g., C₁-C₅ alkyl). In otherembodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄alkyl). In other embodiments, an alkyl comprises one to three carbonatoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises oneto two carbon atoms (e.g., C₁-C₂ alkyl). In other embodiments, an alkylcomprises one carbon atom (e.g., C₁ alkyl). In other embodiments, analkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). Inother embodiments, an alkyl comprises five to eight carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises two to fivecarbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkylcomprises three to five carbon atoms (e.g., C₃-C₄ alkyl). In otherembodiments, the alkyl group is selected from methyl, ethyl, 1-propyl(n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. In general, alkylgroups are each independently substituted or unsubstituted. Eachrecitation of “alkyl” provided herein, unless otherwise stated, includesa specific and explicit recitation of an unsaturated “alkyl” group.Similarly, unless stated otherwise specifically in the specification, analkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is optionally substituted as described for“alkyl” groups.

“Alkylene” or “alkylene chain” generally refers to a straight orbranched divalent alkyl group linking the rest of the molecule to aradical group, such as having from one to twelve carbon atoms, forexample, methylene, ethylene, propylene, i-propylene, n-butylene, andthe like. Unless stated otherwise specifically in the specification, analkylene chain is optionally substituted as described for alkyl groupsherein.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system can contain hydrogen and carbon from five to eighteen carbonatoms, where at least one of the rings in the ring system is fullyunsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electronsystem in accordance with the Hückel theory. The ring system from whicharyl groups are derived include, but are not limited to, groups such asbenzene, fluorene, indane, indene, tetralin and naphthalene. Unlessstated otherwise specifically in the specification, the term “aryl” orthe prefix “ar-” (such as in “aralkyl”) is meant to include arylradicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” or “aryl-alkyl” refers to a radical of the formula —R-arylwhere R^(1c) is an alkylene chain as defined above, for example,methylene, ethylene, and the like. The alkylene chain part of thearalkyl radical is optionally substituted as described above for analkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclicor polycyclic hydrocarbon radical consisting solely of carbon andhydrogen atoms, which includes fused or bridged ring systems, havingfrom three to fifteen carbon atoms. In certain embodiments, acarbocyclyl comprises three to ten carbon atoms. In other embodiments, acarbocyclyl comprises five to seven carbon atoms. The carbocyclyl isattached to the rest of the molecule by a single bond. Carbocyclyl orcycloalkyl is saturated (i.e., containing single C—C bonds, no double ortriple bonds between two carbons) or unsaturated (i.e., containing oneor more double bonds or triple bonds). Examples of saturated cycloalkylsinclude, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referredto as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include,e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.Polycyclic carbocyclyl radicals include, for example, adamantyl,norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carboxylic acid,” “COOH,” or “(C═O)OH” refers to a radical of theformula —COOH. Each recitation of “carboxylic acid,” “COOH,” or“(C═O)OH” provided herein, unless otherwise stated, includes a specificand explicit recitation of an esterified “carboxylic acid,” “COOH,” or“(C═O)OH” group (e.g., or radical thereof). In some embodiments, theesterified carboxylic acid group (or radical thereof) is(C═O)O—C₁-C₄alkyl, wherein alkyl is as defined hereinabove. In someembodiments, “carboxylic acid,” “COOH,” or “(C═O)OH” is COOH. In someembodiments, “carboxylic acid,” “COOH,” or “(C═O)OH” is(C═O)O—C₁-C₄alkyl.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(1c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkenyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(1c) is an alkenylene chain as defined above.The alkenylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(1c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to fluoro, bromo, chloro, or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halogen radicals, as defined above, forexample, trihalomethyl, dihalomethyl, halomethyl, and the like. In someembodiments, the haloalkyl is a fluoroalkyl, such as, for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, thealkyl part of the fluoroalkyl radical is optionally substituted asdefined above for an alkyl group.

The term “heteroalkyl” refers to an alkyl group as defined above inwhich one or more skeletal carbon atoms of the alkyl are substitutedwith a heteroatom (with the appropriate number of substituents orvalencies—for example, —CH₂— may be replaced with —NH— or —O—). Forexample, each substituted carbon atom is independently substituted witha heteroatom, such as wherein the carbon is substituted with a nitrogen,oxygen, sulfur, or other suitable heteroatom. In some instances, eachsubstituted carbon atom is independently substituted for an oxygen,nitrogen (e.g. —NH—, —N(alkyl)-, or —N(aryl)- or having anothersubstituent contemplated herein), or sulfur (e.g. —S—, —S(═O)—, or—S(═O)₂—). In some embodiments, a heteroalkyl is attached to the rest ofthe molecule at a carbon atom of the heteroalkyl. In some embodiments, aheteroalkyl is attached to the rest of the molecule at a heteroatom ofthe heteroalkyl. In some embodiments, a heteroalkyl is a C₁-C₁₈heteroalkyl. In some embodiments, a heteroalkyl is a C₁-C₁₂ heteroalkyl.In some embodiments, a heteroalkyl is a C₁-C₆ heteroalkyl. In someembodiments, a heteroalkyl is a C₁-C₄ heteroalkyl. Representativeheteroalkyl groups include, but are not limited to —OCH₂OMe, or—CH₂CH₂OMe. In some embodiments, heteroalkyl includes alkoxy,alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl,heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unlessstated otherwise specifically in the specification, a heteroalkyl groupis optionally substituted as defined above for an alkyl group.

“Heteroalkylene” refers to a divalent heteroalkyl group defined abovewhich links one part of the molecule to another part of the molecule.Unless stated specifically otherwise, a heteroalkylene is optionallysubstituted, as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(1c)-heterocyclyl where R^(1c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-SH-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(1c)-heteroaryl,where R^(1c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

In general, optionally substituted groups are each independentlysubstituted or unsubstituted. Each recitation of an optionallysubstituted group provided herein, unless otherwise stated, includes anindependent and explicit recitation of both an unsubstituted group and asubstituted group (e.g., substituted in certain embodiments, andunsubstituted in certain other embodiments). Unless otherwise stated,substituted groups may be substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of thepharmacological agents described herein is intended to encompass any andall pharmaceutically suitable salt forms. Exemplary pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supro.

Compositions

The meibomian glands are large sebaceous glands located in the eyelids,and unlike skin, are unassociated with hair. The meibomian glandsproduce the lipid layer of the tear film that protects it againstevaporation of the aqueous phase. The meibomian gland orifice is locatedon the epithelial side of the lid margin, and can be a few hundredmicrons from the mucosal side. The glands are located on both upper andlower eyelids, with higher amounts of the glands on the upper eyelid. Asingle meibomian gland is composed of clusters of secretory acini thatare arranged circularly around a long central duct and connected to itby short ductules. The terminal part of the central duct is lined by aningrowth of the epidermis that covers the free lid margin and forms ashort excretory duct that opens as an orifice at the posterior part ofthe lid margin just anterior to the mucocutaneous junction near theinner lid border. The oily secretion composed of lipids is synthesizedwithin the secretory acini. The lipid secretion is a liquid at near bodytemperature and is delivered to the skin of the lid margin as a clearfluid, called “meibum.” It forms shallow reservoirs on the upper andlower lid margins, and consists of a complex mixture of cholesterol,wax, cholesteryl esters, phospholipids, with small amounts oftriglycerides, triacylglycerols, and hydrocarbons. The separatemeibomian glands are arranged in parallel, and in a single rowthroughout the length of the tarsal plates in the upper and lower lids.The extent of the glands corresponds roughly to the dimensions of thetarsal plates.

The term “keratinized obstruction” as used herein refers to a blockageof the meibomian gland, regardless of the location of the blockage. Insome embodiments, the blockage is complete, whereas in otherembodiments, the blockage is partial. Regardless of the degree ofblockage, such keratinized obstruction leads to meibomian glanddysfunction. In some embodiments, the keratinized obstruction iscomposed of keratinized material and lipids. In some embodiments, thekeratinized obstruction is a blockage at the meibomian gland orifice andexcretory duct. In some embodiments, the keratinized obstruction iscaused by keratinization of the epithelium at the lid margin andmeibomian gland. In certain instances, the keratin obstruction isinfluenced by the migration or aberrant differentiation of stem cells.In some embodiments, the keratinized obstruction results in reduceddelivery of oil to the lid margin and tear film, and stasis inside themeibomian gland that causes increased pressure, resultant dilation,acinar atrophy, and low secretion. In certain instances, keratinizationof the meibomian gland causes degenerative gland dilation and atrophy.

Ocular surface diseases is a group of diseases including, but notlimited to, dry eye syndrome (including evaporative DES and/or aqueousdeficiency DES), blepharitis, keratitis, meibomian gland dysfunction,conjunctivitis, lacrimal gland disorder, contact lens related conditionsand inflammatory, infectious, or autoimmune diseases or disorders of theanterior surface of the eye. The term, “meibomian gland dysfunction,” asused herein, refers to chronic, diffuse abnormality of the meibomianglands, that is characterized by terminal duct obstruction orqualitative or quantitative changes in the glandular secretion, or both.MGD may result in alteration of the tear film, eye irritation symptoms,inflammation, or ocular surface disease. The most prominent aspects ofMGD are obstruction of the meibomian gland orifices and terminal ductsand changes in the meibomian gland secretions.

In some instances, meibomian gland dysfunction (MGD) is a chronic,diffuse abnormality of the meibomian glands, which can be characterizedby terminal duct obstruction and/or qualitative/quantitative changes inthe glandular secretion. Terminal duct obstruction is caused byhyperkeratinization of the ductal epithelium (Nichols et al, Inv. Oph. &Vis. Sci. (2011); 52(4):1922-1929). These alterations in both meibumquality and expression may result in alteration of the tear film,symptoms of eye irritation, and ocular surface disease such asevaporative dry eye. The principal clinical consequence of MGD isevaporative dry eye syndrome and large population based studies (i.e.,Bankok Study and the Shihpai Eye Study) estimate that over 60% ofpatients with dry eye symptoms also have MGD (Schaumberg et al,Investigative Ophthalmology and Visual Science. (2011);52(4):1994-2005).

MGD is a leading contributor of dry eye syndrome. The occurrence of dryeye syndrome is widespread and affects about 20 million patients in theUnited States alone. Dry eye syndrome is a disorder of the ocularsurface resulting from either inadequate tear production or excessiveevaporation of moisture from the surface of the eye. Tears are importantto corneal health because the cornea does not contain blood vessels, andrelies on tears to supply oxygen and nutrients. Tears and the tear filmare composed of lipids, water, and mucus, and disruption of any of thesecan cause dry eye. An inadequate amount of lipids flowing from themeibomian glands as caused by a keratinized obstruction, may causeexcessive evaporation, thereby causing dry eye syndrome.

In some embodiments, altered meibomian gland secretion is detected byphysically expressing the meibomian glands by applying digital pressureto the tarsal plates. In subjects without MGD, the meibum is a pool ofclear oil. In MGD, both the quality and expressibility of the expressedmaterial is altered. The altered meibum is also known as meibomianexcreta and is made up of a mixture of altered secretions andkeratinized epithelial material. In MGD, the quality of expressed lipidvaries in appearance from a clear fluid, to a viscous fluid containingparticulate matter and densely opaque, toothpaste-like material. Themeibomian orifices may exhibit elevations above surface level of thelid, which is referred to as plugging or pouting, and is due toobstruction of the terminal ducts and extrusion of a mixture ofmeibomian lipid and keratinized material.

Obstructive MGD is characterized by all or some of the following: 1)chronic ocular discomfort, 2) anatomic abnormalities around themeibomian gland orifice (which is one or more of the following: vascularengorgement, anterior or posterior displacement of the mucocutaneousjunction, irregularity of the lid margin) and 3) obstruction of themeibomian glands (obstructive findings of the gland orifices by slitlamp biomicroscopy (pouting, plugging or ridge), decreased meibumexpression by moderate digital pressure).

Current methods for assessing and monitoring MGD symptoms include, butare not limited to patient questionnaires, meibomian gland expression,tear stability break up time, and determining the number of patentglands as seen by digital expression.

In some embodiments, the symptoms of a patient are assessed by askingthe patient a series of questions. Questionnaires allow the assessmentof a range of symptoms associated with ocular discomfort. In someembodiments, the questionnaire is the SPEED questionnaire. The SPEEDquestionnaire assesses frequency and severity of a patient's dry eyesymptoms. It examines the occurrence of symptoms on the current day,past 72 hours and past three months. A SPEED score is tallied based onthe patient's answers to the questions, to give a range of severity ofthe patient's symptoms.

The SPEED questionnaire includes questions such as the following: 1)what dry eye symptoms are you experiencing, and when do they occur? 2)how frequently do you experience dryness, grittiness, or scratchiness inyour eyes? 3) how often do you experience soreness or irritation of theeyes? 4) how often do you experience burning or watering of the eyes? 5)how often do you experience eye fatigue? and 6) how severe are thesymptoms?

Meibomian gland expressibility is optionally determined to assess themeibomian gland function. In normal patients, meibum is a clear to lightyellow oil. Meibum is excreted from the glands when digital pressure isplaced on the glands. Changes in meibomian gland expressibility are onepotential indicator of MGD. In some embodiments, during expression,quantifying the amount of physical force applied during expression ismonitored in addition to assessing lipid volume and lipid quantity.

Tear stability break up time (TBUT) is a surrogate marker for tearstability. Tear film instability is a core mechanism in dry eye and MGD.Low TBUT implies a possibility of lipid layer compromise and MGD. TBUTis optionally measured by examining fluorescein breakup time, as definedas the time to initial breakup of the tear film after a blink.Fluorescein is optionally applied by wetting a commercially availablefluorescein-impregnated strip with saline, and applied to the inferiorfornix or bulbar conjuctiva. The patient is then asked to blink severaltimes and move the eyes. The break up is then analyzed with a slit lamp,a cobalt blue filter, and a beam width of 4 mm. The patient isinstructed to blink, and the time from upstroke of the last blink to thefirst tear film break or dry spot formation is recorded as ameasurement.

Other methods for assessing MGD symptoms, include but are not limitedto, Schirmer test, ocular surface staining, lid morphology analysis,meibography, meibometry, interferometry, evaporimetry, tear lipidcomposition analysis, fluorophotometry, meiscometry, osmolarityanalysis, indices of tear film dynamics, evaporation and tear turnover.

Current treatments for MGD include lid warming, lid massage, lidhygiene, lid expression and meibomian gland probing. Pharmacologicalmethods, prior to those described herein, have not been used.

Lid hygiene is considered the primary treatment for MGD and consists ofthree components: 1) application of heat, 2) mechanical massage ofeyelids and 3) cleansing the eyelid. Eyelid warming procedures improvemeibomian gland secretion by melting the pathologically alteredmeibomian lipids. Warming is achieved by warm compresses or devices.Mechanical lid hygiene includes the use of scrubs, mechanical expressionand cleansing with various solutions of the eyelashes and lid margins.Lid margins are optionally also cleansed with hypoallergenic bar soap,dilute infant shampoo or commercial lid scrubs. Physical expression ofmeibomian glands is performed in a physician's office or is performed bythe patient at home. The technique varies from gentle massage of thelids against the eyeball to forceful squeezing of the lids eitheragainst each other or between a rigid object on the inner lid surfaceand a finger, thumb, or rigid object (such as a glass rod, cotton swab,or metal paddle) on the outer lid surface. The rigid object on the innerlid surface protects the eyeball from forces transferred through theeyelid during expression and to offer a stable resistance, to increasethe amount of force that is applied to the glands.

Eyelid warming is limited because the warming melts the lipids, but doesnot address movement of the keratinized material. Further, eyelidwarming induces transient visual degradation due to corneal distortion.Mechanical lid hygiene is also limited because the force needed toremove an obstruction can be significant, resulting in significant painto the patient. The effectiveness of mechanical lid hygiene is limitedby the patient's ability to tolerate the associated pain during theprocedure. Other treatments for MGD are limited.

Physical opening of meibomian glands obstruction by meibomian glandexpression is an acceptable method to improve meibomian gland secretionand dry eye symptoms. In addition probing of the meibomian gland canalhas been used to open the obstructed canal. Both methods, expression andprobing, are limited, however, by the pain induced by the procedure, thepossible physical insult to the gland and canal structures and theirshort lived effect estimated at days and weeks. Therefore, methods areneeded to improve patient comfort, which will not cause harm to themeibomian glands and canals, that will reduce the dependency on frequentoffice visits and improve secretion of meibum.

U.S. Pat. No. 9,463,201 entitled, “Compositions and methods for thetreatment of meibomian gland dysfunction” describes a method fortreating meibomian gland dysfunction involving the topicaladministration of a therapeutically-effective amount of at least onekeratolytic agent in an ophthalmically-acceptable carrier. The patentincludes keratolytic agents that are inorganic selenium (Se) compoundssuch as selenium disulfide (SeS₂) or organoselenium compounds such asEbselen (2-Phenyl-1,2-benzoselenazol-3-one). This agent would treat theunderlying cause of MGD, but not a “plus” inflammatory disease asdescribed by the DEWS report on MGD.

The role of inflammation in the etiology of MGD is controversial. Theterms posterior blepharitis and MGD are not synonymous. Posteriorblepharitis describes inflammatory conditions of the posterior lidmargin and has various causes, of which MGD can be one possible cause(Nichols et al 2011). In its earliest stages, MGD is not associated withclinical signs characteristic of posterior blepharitis. As MGDprogresses, an MGD-related posterior blepharitis is said to be present.MGD-related posterior blepharitis affects the meibomian glands andmeibomian gland orifices. MGD-related posterior blepharitis ischaracterized by flora changes, esterase and lipase release, lipidchanges, and eyelid inflammation. Hyperkeratinization of the meibomiangland epithelium (thickening of the lining of the glands) may lead toobstruction and a decrease in the quantity of meibomian gland secretionsand may be responsible for MGD-related posterior blepharitis. Diagnosisof MGD-related posterior blepharitis includes meibomian gland expressionwith demonstration of an altered quality of expressed secretions, and/orby a loss of gland functionality (decreased or absent expressibility).The TFOS report on Meibomian Gland Disease specifically notes thatanterior blepharitis and exacerbated inflammatory ocular surface diseaseare “plus” diseases to MGD which are managed by topical, ocular steroids(Nichols et al 2011). Since these “plus” conditions can be present invarious levels of severity from early to late MGD there is a need fortreatments and/or combinations of treatments that can target both theunderlying non-inflammatory pathophysiology of MGD and inflammationassociated with these comorbid conditions.

MGD-related inflammatory eye disease may comprise a different mechanismthan blepharitis-related MGD. MGD-related inflammatory eye disease ischaracterized by an inflammatory cascade involving activation andmigration of T lymphocytes to the inflamed tissue. T lymphocyteinfiltration may result in lacrimal gland stimulation and upregulationof cytokines. Exemplary cytokines that may be involved in MGD-relatedinflammatory eye disease include, but are not limited to, interleukin-1,interleukin-4, interleukin-6, interleukin-8, interferon gamma,macrophage inflammatory protein 1 alpha, and tumor necrosis factoralpha. Kinase pathways including the mitogen activated protein kinase(MAPK) pathway are also activated in the inflammatory cascade. Theinflammatory process results in loss of mucin-producing goblet cells anddestruction of the ocular surface that can lead to further damage.

Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), isconsidered a self-sustaining disease that is progressively disconnectedfrom its initial cause. Dry eye syndrome is associated with inflammationat the ocular surface and periocular tissue. Inflammation ischaracterized by the activation and migration of T lymphocytes to theinflamed tissue including in the conjunctiva and lacrimal glands.Inflammatory cytokines, chemokines, and matrix metalloproteinase havealso been identified as being increased.

Animal models of dry eye disease have been established and reviewed(Barabino, et al, (Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)).Barabino, et al, (Invest. Ophthalmol. Vis. Sci. 2005, 46:2766-2771)described a model wherein exposure of normal mice to a low-humidityenvironment in a controlled-environment chamber leads to significantalterations in tear secretion, goblet cell density, and acquisition ofdry eye-related ocular surface signs. However, no single animal modeladequately accounts for the immune, endocrine, neuronal andenvironmental factors which contribute to dry eye pathogenesis.

Anti-inflammatory agents may be used to treat ocular surface diseases ordisorders including dry eye syndrome. Corticosteroids are an effectiveanti-inflammatory therapy in dry eye disease. For example, in a 4-week,double-masked, randomized study in 64 patients with dry eye and delayedtear clearance, loteprednol etabonate 0.5% ophthalmic suspension(Lotemax [Bausch and Lomb, Rochester, N.Y.]), QID, was found to be moreeffective than its vehicle in improving some signs and symptoms(Pflugfelder et al, Am J Ophthalmol (2004); 138:444-57). The TFOS 2007report on dry eye disease went so far as to conclude that, “In the USFederal Regulations, ocular corticosteroids receiving “class labeling”are indicated for the treatment “ . . . of steroid responsiveinflammatory conditions of the palpebral and bulbar conjunctiva, corneaand anterior segment of the globe such as allergic conjunctivitis, acnerosacea, superficial punctate keratitis, herpes zoster keratitis,iritis, cyclitis, selected infective conjunctivitis, when the inherenthazard of steroid use is accepted to obtain an advisable diminution inedema and inflammation.” KCS, in some instances, is included in thislist of steroid-responsive inflammatory conditions (Therapy Subcommitteeof the International Dry Eye WorkShop, 2007. Management and Therapy ofDry Eye Disease: Report of the Management and Therapy Subcommittee ofthe International Dry Eye WorkShop (2007). 2007; 5: 163-178).” While theUS FDA does not agree with this conclusion, short courses of steroids,especially Lotemax, can be used to treat inflammation associated withdry eye disease.

Other anti-inflammatory agents include nonsteroidal anti-inflammatorydrugs (NSAIDs). NSAIDs inhibit the activity of cyclooxygenases includingcyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are enzymesinvolved in the synthesis of prostaglandins and thromboxanes fromarachidonic acid. Prostaglandin and thromboxane signaling are involvedin inflammation and immune modulation. In some cases, NSAIDs are usedfor treating dry eye disease by treating the inflammation at the ocularsurface.

Treatment of dry eye is also accomplished through agents that enhancetear fluid and mucin production. For example, agonists of the P2Y₂receptor have been shown to increase tear fluid and mucin secretion. Themechanism is thought to involve P2Y₂ signaling to raise intracellularcalcium and open chloride channels in the apical membrane. The P2Y₂receptor belongs to the family of purinergic receptors, which have beenclassified into P1 receptors and P2 receptors on the basis of theirnative agonism by purine nucleosides and purine and pyrimidinenucleotides, respectively. P2 receptors are further distinguishedphysiologically into two types: P2X receptors and P2Y receptors. The P2Yreceptors are involved in diver signaling including plateletaggregation, immunity, lipid metabolism, and bone activity. Severalstudies have also demonstrated the presence of P2X and P2Y receptors inocular tissues, including the retina, ciliary body, and lens. Thesestudies indicate that P2Y₂ receptors appear to be the main subtype ofpurinergic receptor located at the ocular surface. P2Y₂ receptors havealso been demonstrated to be localized in ocular tissues in theconjunctival epithelial goblet and serous cells and meibomian glandacinus and ductal epithelial cells of the rhesus macaque.

Azithromycin

Azithromycin is a macrolide antibiotic with a 15-membered ring. Itschemical name is(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methylα-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-onehaving a molecular weight of 749, and an empirical formula isC₃₈H₇₂N₂O₁₂. The structural formula is:

Azithromycin acts by binding to the SOS ribosomal subunit of susceptiblemicroorganisms and interfering with microbial protein synthesis. In thetopical ophthalmic setting, Azithromycin is formulated as a 1% solutionof pH 6.3 comprising benzalkonium chloride. Azithromycin is indicatedfor the treatment of bacterial conjunctivitis caused by susceptibleisolates of the following microorganisms: Hoemophilus influenzoe,Staphylococcus aureus, Streptococcus mitis group, or Streptococcuspneumoniae. Further information about azithromycin ophthalmic solutioncan be found in, for example, U.S. Pat. Nos. 6,239,113, 6,569,443, or7,056,893.

Described herein are compounds (e.g., keratolytic conjugates and/or dualacting-agents) which address simultaneously the non-inflammatorykeratolytic blockage component of meibomian gland dysfunction and theinflammation associated dry eye disease including aqueous deficiency. Insome embodiments, a compound provided herein is useful as either anacute therapy (e.g., by a trained specialist or physician) or as achronic therapy (e.g., in the hands of a patient, or alternatively, by atrained specialist or physician). A compound provided herein is tested,in some embodiments, using the assays and methods described herein(e.g., as described in the examples). In some embodiments, a compoundprovided herein represents a significant advance in the art as thefirst-order metabolites obtained from metabolism of the agents areoperative against both the keratolytic and the inflammatory component ofdry eye disease.

Provided in some embodiments herein is a compound, having the structureof Formula (I):

wherein,

-   -   each R^(Q) is independently H, R^(N), substituted or        unsubstituted alkyl, or substituted or unsubstituted        heteroalkyl, wherein at least one R^(Q) is R^(N);    -   R^(N) is D-L^(a)-;    -   D is a keratolytic agent; and    -   L^(a) is a linker,

or a stereoisomer thereof, or a pharmaceutically acceptable salt orsolvate thereof.

In some embodiments, the compound has a structure represented by:

In some embodiments, provided herein is a compound, having the structureof Formula (I-A):

wherein,

-   -   R′ is D-L^(a)-;    -   D is a keratolytic agent; and    -   L^(a) is a linker,

or a stereoisomer thereof, or a pharmaceutically acceptable salt orsolvate thereof.

In some embodiments, L^(a) comprises one or more linker group, eachlinker group being independently selected from the group consisting of abond, —O—, —S—, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl),disulfide, ester, and carbonyl (>C═O). In some embodiments, thekeratolytic agent comprises one or more groups of the group (e.g.,keratolytic group, such as a group conferring keratolytic activity),each group (e.g., keratolytic group) being independently selected fromthe group consisting of thiol, disulfide, selenium (e.g., selenide,diselenide), carboxylic acid or a group which can be metabolized to acarboxylic acid.

In some embodiments, R′ is alkyl or heteroalkyl substituted with atleast one oxo, and further optionally substituted.

In some embodiments, R′ is:

-   -   wherein:    -   z is 1-6;    -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and R⁹        are taken together with the atoms to which they are attached to        form a C₃-C₅-cycloalkyl; and    -   R¹² is H, alkyl, aryl or heteroalkyl, the alkyl, aryl, or        heteroalkyl being optionally substituted,    -   or a stereoisomer thereof, or a pharmaceutically acceptable salt        or solvate thereof.

In some embodiments, the alkyl or heteroalkyl of R¹² is substituted withone or more substituent, each substituent being independently selectedfrom the group consisting of alkyl, heteroalkyl, hydroxyl, thiol,thioether, disulfide, seleno, selenol, sulfone, amide, halo, oxo,heterocyclyl, and cycloalkyl, wherein the heterocyclyl and cycloalkyl isoptionally substituted (e.g., with one or more substituent selected fromthe group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether,disulfide, selenol, sulfone, amide, halo, and oxo).

In some embodiments, z is described elsewhere herein.

In some embodiments, each R⁸ and R⁹ is described elsewhere herein.

In some embodiments, provided herein is a compound having the structureof Formula (Ia):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof,

wherein,

-   -   L is bond, —(C═O)(OCR⁸R⁹)₂—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;        -   z is 1-6;    -   X is absent or —O—; and    -   R is substituted alkyl, substituted heteroalkyl, or substituted        heterocycloalkyl,    -   wherein the substituted alkyl is substituted with one or more        alkyl substituent, at least one alkyl substituent being        independently selected from the group consisting of substituted        or unsubstituted cycloalkyl and substituted heterocycloalkyl,        and the substituted heteroalkyl is substituted with one or more        heteroalkyl substituent, at least one heteroalkyl substituent        being independently selected from the group consisting of —COOH,        substituted heterocycloalkyl, and thioalkyl, the substituted        alkyl or substituted heteroalkyl being further optionally        substituted.

In some embodiments, provided herein is a compound having the structureof Formula (Ia):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof,

wherein,

-   -   L is bond, —(C═O)(OCR⁸R⁹)_(z)—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;        -   z is 1-6;    -   X is absent or —O—; and    -   R is substituted (e.g., straight or branched) alkyl, substituted        (e.g., straight or branched) heteroalkyl, or substituted        heterocycloalkyl (e.g., (N—) substituted with alkyl further        substituted with oxo and thiol), the substituted alkyl being        substituted with one or more (alkyl) substituent, at least one        (alkyl) substituent being independently selected from the group        consisting of —SH, substituted or unsubstituted (e.g.,        unsaturated) cycloalkyl, and dithiolanyl oxide, or the        substituted heteroalkyl being substituted with one or more        (heteroalkyl) substituent, at least one (heteroalkyl)        substituent being independently selected from the group        consisting of —SH, —COOH, and thioalkyl, the substituted alkyl,        substituted heteroalkyl, or substituted heterocycloalkyl being        further optionally substituted.

In some embodiments, L is bond. In some embodiments, L is—(C═O)(OCR⁸R⁹)_(z)— or —(C═O)(OCR⁸R⁹)_(z)O—. In some embodiments, L is—(C═O)(OCR⁸R⁹)_(z)—. In some embodiments, L is —(C═O)(OCR⁸R⁹)_(z)O—. Insome embodiments z is 1-3. In some embodiments, z is 1. In someembodiments, each R⁸ and R⁹ is independently H or C₁-C₃-alkyl. In someembodiments, each R⁸ is H and each R⁹ is C₁-C₃-alkyl. In someembodiments, each R⁸ is H and each R⁹ is CH₃. In some embodiments, R⁸and R⁹ are H. In some embodiments, L is —(C═O)OCH(CH₃)—. In someembodiments, L is —(C═O)OCH(CH₃)O—.

In some embodiments, X is absent. In some embodiments, X is —O—.

In some embodiments, L is —(C═O)OCH(CH₃)— or —(C═O) OCH(CH₃)O— and X isabsent or —O—.

In some embodiments, L is —(C═O)OCH(CH₃)— and X is absent.

In some embodiments, L is —(C═O)OCH(CH₃)— and X is —O—.

In some embodiments, L is bond and X is absent.

In some embodiments, R is substituted (e.g., straight or branched)alkyl, the (e.g., straight or branched) alkyl being substituted with oneor more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of hydroxy, optionallysubstituted alkoxy (e.g., optionally substituted with oxo and hydroxy oroxo and C₁-C₃ alkoxy)), oxo, optionally substituted alkyl (e.g.,optionally substituted with alkoxy further optionally substituted withoxo, C₁-C₄ alkyl, and/or hydroxy), optionally substitutedheterocycloalkyl (e.g., optionally substituted dioxane (e.g., 1,3dioxanyl optionally substituted with methyl), dithiolanyl, ordithiolanyl oxide), hydroxyalkyl, thiol, acetamide, substitutedunsaturated cycloalkyl (e.g., being substituted with one or more C₁-C₄alkyl), and amino.

In some embodiments, R is substituted (e.g., straight or branched)alkyl, the (e.g., straight or branched) alkyl being substituted with oneor more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of thiol, amino,acetamide, substituted unsaturated cycloalkyl (e.g., being substitutedwith one or more C₁-C₄ alkyl), and substituted heterocycloalkyl (e.g.,dithiolanyl oxide).

In some embodiments, R is substituted alkyl, the alkyl being substitutedwith substituted heterocycloalkyl.

In some embodiments, R is substituted alkyl. In some embodiments, R issubstituted alkyl, wherein the substituted alkyl is substituted with oneor more alkyl substituent, at least one alkyl substituent beingindependently selected from the group consisting of substituted orunsubstituted cycloalkyl and substituted heterocycloalkyl. In someembodiments, R is substituted alkyl, the alkyl being substituted withsubstituted heterocycloalkyl. In some embodiments, R is substitutedalkyl, the alkyl being substituted with 1,2-dithiolanyl oxide. In someembodiments, R is substituted alkyl, the alkyl being substituted withsubstituted C₅-C₁₅ heterocycloalkyl (e.g., C₁₂ heterocycloalkyl with oneor more disulfide and one or more amide within the heterocycloalkylring) being substituted with one or more substituent, at least onesubstituent being independently selected from the group consisting ofC₁-C₃ alkyl, oxo, and —COOH. In some embodiments, the substituted alkylis further optionally substituted.

In some embodiments, L is bond, X is absent, and R is substituted (e.g.,straight or branched) alkyl, the (e.g., straight or branched) alkylbeing substituted with one or more (alkyl) substituent, each (alkyl)substituent being independently selected from the group consisting ofthiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., beingsubstituted with one or more C₁-C₄ alkyl), and substitutedheterocycloalkyl (e.g., dithiolanyl oxide).

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or more —C—O—C— (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or more ester, one or morecarbonate, one or more amide, and/or one or more disulfide (e.g., withinthe (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl comprising one or more ester, one or more amide, and/or oneor more disulfide (e.g., within the (e.g., linear or branched)heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one carbonate (e.g., within the (e.g.,linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two ester (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one ester (e.g., within the (e.g.,linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one ester and one carbonate (e.g.,within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two ester and one amide (e.g.,within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one ester and one amide (e.g., withinthe (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two amide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two disulfide (e.g., within the(e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one disulfide (e.g., within the (e.g.,linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl comprising one or two disulfide and one ester(e.g., within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted or unsubstituted (e.g., linear orbranched) heteroalkyl containing one or two disulfide and one amide(e.g., within the (e.g., linear or branched) heteroalkyl chain).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of optionally substituted C₁-C₆ alkyl, acetamide, hydroxy,heterocycloalkyl, thiol, thioalkyl, amino, and carboxylic acid.

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of thioalkyl, amino, carboxylic acid, C₁-C₆ alkyl, acetamide,thiol, oxo, and optionally substituted (e.g., N-attached)heterocycloalkyl (e.g., optionally substituted with carboxylic acid).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with substituted C₁-C₆ alkyl, the C₁-C₆ alkyl beingsubstituted with heteroalkyl being further optionally substituted withone or more additional substituent, each additional substituent beingindependently selected from the group consisting of hydroxy, carboxylicacid, optionally substituted N-substituted pyrrolidinyl (e.g.,optionally substituted with carboxylic acid)).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with heterocycloalkyl. In some embodiments, R is substituted(e.g., linear or branched) heteroalkyl, the (e.g., linear or branched)heteroalkyl being substituted with 1,2-dithiolane, 1,2-dithiolane oxide,optionally substituted dioxane (e.g., optionally substituted with one ormore C₁-C₆ alkyl), (e.g., N-substituted) pyrrolidine (e.g., substitutedwith alkyl further substituted with oxo, thiol, and C₁-C₃ alkyl), orsubstituted (e.g., N-attached) pyrrolidine (e.g., substituted withcarboxylic acid).

In some embodiments, R is substituted (e.g., linear or branched)heteroalkyl, the (e.g., linear or branched) heteroalkyl beingsubstituted with acetamide and carboxylic acid.

In some embodiments, R is substituted heteroalkyl, the heteroalkyl beingsubstituted with —COOH, —CH₂SH, and/or optionally substituted N-attachedheterocycloalkyl, and being further substituted with one or more othersubstituent, each substituent being independently selected from thegroup consisting of acetamide, amino, C₁-C₆ alkyl, thiol, and oxo.

In some embodiments, R is substituted heteroalkyl comprising twodisulfide bonds within the heteroalkyl chain, the heteroalkyl beingsubstituted with —COOH or substituted N-attached heterocycloalkyl, andbeing further substituted with one or more other substituent, eachsubstituent being independently selected from the group consisting ofacetamide and C₁-C₆ alkyl.

In some embodiments, R is substituted heteroalkyl comprising onedisulfide bond within the heteroalkyl chain, the heteroalkyl beingsubstituted with acetamide, —COOH, and —SH.

In some embodiments, L is bond, X is absent, and R is substituted (e.g.,linear or branched) heteroalkyl, the (e.g., linear or branched)heteroalkyl being substituted with one or more (heteroalkyl)substituent, each (heteroalkyl) substituent being independently selectedfrom the group consisting of thioalkyl, amino, carboxylic acid, C₁-C₆alkyl, acetamide, thiol, oxo, and optionally substituted (e.g.,N-attached) heterocycloalkyl (e.g., optionally substituted withcarboxylic acid).

In some embodiments, R is:

In some embodiments, R is substituted branched heteroalkyl.

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R—X-L is:

In some embodiments, R—X-L is:

In some embodiments R—X-L is:

In some embodiments, R is substituted heterocycloalkyl (e.g.,N-substituted with alkyl further substituted with oxo and thiol).

In some embodiments, R is heterocycloalkyl N-substituted with alkyl, thealkyl being further substituted with oxo and/or thiol.

In some embodiments, R is:

In some embodiments, R comprises a radical of one or more keratolyticgroup (e.g., each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Lip), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R comprises a radical of one or more keratolyticgroup, each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Lip), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc).

In some embodiments, R comprises a thiol radical of one or morekeratolytic group, each thiol radical of the one or more keratolyticgroup being independently selected from the group consisting of a thiolradical of thioglycolic acid (TGA), a thiol radical of thiolactic acid(TLac), a thiol radical of dihydrolipoic acid (diHLip), a thiol radicalof N-acetyl cysteine (NAC), a thiol radical of cysteine (Cys), a thiolradical of glutathione (GSH), a thiol radical of captopril (Cap), and athiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHLip-Lipox]•.

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•, [diHLip-Cap-Cap]•,[diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•, [diHLip-Lipox-Lipox]•,and [diHLip-Lipox]•.

Unless stated otherwise, a radical (or .) is molecule having unpairedelectrons. In some embodiments, the radical is a radical of a heteroatom(e.g., —O., —N., or —S.). In some embodiments, the radical (e.g., themolecule having unpaired electron) is paired with another unpairedelectron of another molecule to form paired electrons. In someembodiments, a radical of a keratolytic agent provided herein is pairedwith any compound provided herein. In some embodiments, a first radicalof a keratolytic agent provided herein is paired with a second radicalof a keratolytic provided herein.

In some embodiments, the radical of the keratolytic group is the pointof attachment of R to the rest of the molecule. In some embodiments,(the thiol radical of) R each independently attach to the rest of themolecule to form a disulfide bond.

In some embodiments, R is:

In some embodiments, R is:

In some embodiments, R is the radical recited in Compound 1.

In some embodiments, R is the radical recited in Compound 2.

In some embodiments, R is the radical recited in Compound 3.

In some embodiments, R is the radical recited in Compound 4.

In some embodiments, R is the radical recited in Compound 5.

In some embodiments, R is the radical recited in Compound 6.

In some embodiments, R is the radical recited in Compound 7.

In some embodiments, R is the radical recited in Compound 8.

In some embodiments, R is the radical recited in Compound 9.

In some embodiments, R is the radical recited in Compound 10.

In some embodiments, R is the radical recited in Compound 11.

In some embodiments, R is the radical recited in Compound 12.

In some embodiments, R is the radical recited in Compound 13.

In some embodiments, R is the radical recited in Compound 14.

In some embodiments, R is the radical recited in Compound 15.

In some embodiments, R is the radical recited in Compound 16.

In some embodiments, R is the radical recited in Compound 17.

In some embodiments, R is the radical recited in Compound 18.

In some embodiments, R is the radical recited in Compound 19.

In some embodiments, R is the radical recited in Compound 20.

In some embodiments, R is the radical recited in Compound 24.

In some embodiments, R is the radical recited in Compound 25.

In some embodiments, R is the radical recited in Compound 26.

In some embodiments, R is the radical recited in Compound 28.

In some embodiments, R is the radical recited in Compound 29.

In some embodiments, R is the radical recited in Compound 31.

In some embodiments, R is the radical recited in Compound 32.

In some embodiments, R is the radical recited in Compound 33.

In some embodiments, R is the radical recited in Compound 34.

In some embodiments, R is the radical recited in Compound 35.

In some embodiments, R is the radical recited in Compound 36.

In some embodiments, R is the radical recited in Compound 37.

In some embodiments, R is the radical recited in Compound 38.

In some embodiments, R is the radical recited in Compound 40.

In some embodiments, R is the radical recited in Compound 41.

In some embodiments, R is the radical recited in Compound 42.

In some embodiments, R is the radical recited in Compound 43.

In some embodiments, R is the radical recited in Compound 44.

In some embodiments, R is the radical recited in Compound 45.

In some embodiments, R is the radical recited in Compound 46.

In some embodiments, R is the radical recited in Compound 47.

In some embodiments, R is the radical recited in Compound 48.

In some embodiments, R is the radical recited in Compound 49.

In some embodiments, R is the radical recited in Compound 50.

In some embodiments, R is the radical recited in Compound 51.

In some embodiments, the compound is other than a compound having thestructure:

Provided in some embodiments herein is a compound having the structureof Formula (Ib):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof,wherein:

-   -   L is bond, —(C═O)(OCR⁸R⁹)_(z)—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;        -   z is 1-6;    -   X is absent or —O—; and    -   R^(x) is:

-   -   R^(1a) and R^(1b) are each independently —H or —SR^(1c);        -   each R^(1c) is independently substituted or unsubstituted            (e.g., straight or branched) alkyl (e.g., substituted with            one or more (alkyl) substituent, each (alkyl) substituent            being independently selected from the group consisting of            carboxylic acid, —SH, thioalkyl, acetamide, amino, oxo,            optionally substituted heterocycloalkyl (e.g., N-attached            pyrrolidinyl substituted with —COOH)) or substituted or            unsubstituted (e.g., straight or branched) heteroalkyl            (e.g., substituted with one or more (heteroalkyl)            substituent, each (heteroalkyl) substituent being            independently selected from the group consisting of            carboxylic acid, amino, thioalkyl, thiol, acetamide, and            C₁-C₃ alkyl);    -   each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) is        independently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or two of R^(2a) and R^(2b),        R^(2c) and R^(2d), or R^(2e) and R^(2f) are taken together with        the atoms to which they are attached to form a C₃-C₅-cycloalkyl;    -   m is an integer from 1-10; and    -   n and o are each independently an integer from 0-3.

Provided in some embodiments herein is a compound having the structureof Formula (Ib):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof, wherein:

-   -   L is bond, —(C═O)(OCR⁸R⁹)—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;        -   z is 1-6;    -   X is absent or —O—; and    -   R^(x) is:

-   -   R^(1a) and R^(1b) are each independently —H or —SR^(1c);        -   each R^(1c) is independently substituted or unsubstituted            (e.g., straight or branched) alkyl (e.g., substituted with            one or more (alkyl) substituent, each (alkyl) substituent            being independently selected from the group consisting of            carboxylic acid, —SH, thioalkyl, acetamide, amino, oxo,            optionally substituted heterocycloalkyl (e.g., N-attached            pyrrolidinyl substituted with —COOH)) or substituted or            unsubstituted (e.g., straight or branched) heteroalkyl            (e.g., substituted with one or more (heteroalkyl)            substituent, each (heteroalkyl) substituent being            independently selected from the group consisting of            carboxylic acid, amino, thioalkyl, thiol, acetamide, and            C₁-C₃ alkyl);    -   each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) is        independently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or two of R^(2a) and R^(2b),        R^(2c) and R^(2d), or R^(2e) and R^(2f) are taken together with        the atoms to which they are attached to form a C₃-C₅-cycloalkyl;    -   m is an integer from 1-10; and    -   n and o are each independently an integer from 1-3.

In some embodiments, o is 0.

In some embodiments, o is 0, and R^(x) is:

In some embodiments, o is 0 and n is 2.

In some embodiments, o is 0, n is 2, and R^(x) is:

In some embodiments, o is 0 and n is 1.

In some embodiments, o is 0, n is 1, and R^(x) is:

In some embodiments, m is an integer from 3-5.

In some embodiments, each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), andR^(2f) is independently H, halogen, C₁-C₃alkyl, or C₁-C₃haloalkyl. Insome embodiments, each R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), andR^(2f) is H.

In some embodiments, R^(x) is:

-   -   wherein:        -   R^(1a) and R^(1b) are each independently —H or —SR^(1c); and            -   each R^(1c) is independently substituted or                unsubstituted (e.g., straight or branched) alkyl (e.g.,                substituted with one or more (alkyl) substituent, each                (alkyl) substituent being independently selected from                the group consisting of carboxylic acid, —SH, thioalkyl,                acetamide, amino, oxo, optionally substituted                heterocycloalkyl (e.g., N-attached pyrrolidinyl                substituted with —COOH)) or substituted or unsubstituted                (e.g., straight or branched) heteroalkyl (e.g.,                substituted with one or more (heteroalkyl) substituent,                each (heteroalkyl) substituent being independently                selected from the group consisting of carboxylic acid,                amino, thioalkyl, thiol, acetamide, and C₁-C₃ alkyl).

In some embodiments, R^(x) is:

-   -   wherein:        -   R^(1a) and R^(1b) are each independently —H or —SR^(1c); and            -   each R^(1c) is independently substituted or                unsubstituted (e.g., straight or branched) alkyl (e.g.,                substituted with one or more (alkyl) substituent, each                (alkyl) substituent being independently selected from                the group consisting of carboxylic acid, —SH, thioalkyl,                acetamide, amino, oxo, optionally substituted                heterocycloalkyl (e.g., N-attached pyrrolidinyl                substituted with —COOH)) or substituted or unsubstituted                (e.g., straight or branched) heteroalkyl (e.g.,                substituted with one or more (heteroalkyl) substituent,                each (heteroalkyl) substituent being independently                selected from the group consisting of carboxylic acid,                amino, thioalkyl, thiol, acetamide, and C₁-C₃ alkyl).

In some embodiments, R^(1a) is —H or —SR^(1c) and R^(1b) is —SR^(1c), orR^(1a) is —SR^(1a) and R^(1b) is —H or —SR^(1c). In some embodiments,R^(1a) and R^(1b) are each —SR^(1c).

In some embodiments, R^(1a) and R^(1b) each independently comprise aradical of one or more keratolytic group (e.g., each radical of the oneor more keratolytic group being independently selected from the groupconsisting of a radical of glycolic acid (GA), a radical of thioglycolicacid (TGA), a radical of lactic acid (Lac), a radical of thiolactic acid(TLac), a radical of lipoic acid (Lip), a radical of lipoic acidsulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radicalof N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical ofglutathione (GSH), a radical of captopril (Cap), and a radical ofbucillamine (Buc)).

In some embodiments, R^(1a) and R^(1b) are each independently a radicalof one or more keratolytic group, each radical of the one or morekeratolytic group being independently selected from the group consistingof a radical of glycolic acid (GA), a radical of thioglycolic acid(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid(TLac), a radical of lipoic acid (Lip), a radical of lipoic acidsulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radicalof N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical ofglutathione (GSH), a radical of captopril (Cap), and a radical ofbucillamine (Buc).

In some embodiments, R^(1a) and R^(1b) each independently comprise a(thiol) radical of one or more keratolytic group, each (thiol) radicalof the one or more keratolytic group being independently selected fromthe group consisting of a (thiol) radical of thioglycolic acid (TGA), a(thiol) radical of thiolactic acid (TLac), a (thiol) radical ofdihydrolipoic acid (diHLip), a (thiol) radical of N-acetyl cysteine(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical ofglutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol)radical of bucillamine (Buc).

In some embodiments, R^(1a) and R^(1b) are each independently a thiolradical of one or more keratolytic group, each thiol radical of the oneor more keratolytic group being independently selected from the groupconsisting of a thiol radical of thioglycolic acid (TGA), a thiolradical of thiolactic acid (TLac), a thiol radical of dihydrolipoic acid(diHLip), a thiol radical of N-acetyl cysteine (NAC), a thiol radical ofcysteine (Cys), a thiol radical of glutathione (GSH), a thiol radical ofcaptopril (Cap), and a thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHLip-Lipox]•.

Unless stated otherwise, a radical (or .) is molecule having unpairedelectrons. In some embodiments, the radical is a radical of a heteroatom(e.g., —O, —N., or —S.). In some embodiments, the radical (e.g., themolecule having unpaired electron) is paired with another unpairedelectron of another molecule to form paired electrons. In someembodiments, a radical of a keratolytic agent provided herein is pairedwith any compound provided herein. In some embodiments, a first radicalof a keratolytic agent provided herein is paired with a second radicalof a keratolytic provided herein.

In some embodiments, the thiol radical of the keratolytic group is thepoint of attachment of R^(1a) and/or R^(1b) to the rest of the molecule.In some embodiments, R^(1a) and/or R^(1b) attach to the rest of themolecule to form a disulfide bond.

In some embodiments, R^(1a) and R^(1b) are each independently —H or:

In some embodiments, R^(1a) and R^(1b) are the same. In someembodiments, R^(1a) and R^(1b) are different.

In some embodiments, R^(x) is:

-   -   wherein:        -   each R^(1c) is independently substituted or unsubstituted            (e.g., straight or branched) alkyl (e.g., substituted with            one or more (alkyl) substituent, each (alkyl) substituent            being independently selected from the group consisting of            carboxylic acid, —SH, thioalkyl, acetamide, amino, oxo,            optionally substituted heterocycloalkyl (e.g., N-attached            pyrrolidinyl substituted with —COOH)) or substituted or            unsubstituted (e.g., straight or branched) heteroalkyl            (e.g., substituted with one or more (heteroalkyl)            substituent, each (heteroalkyl) substituent being            independently selected from the group consisting of            carboxylic acid, amino, thioalkyl, thiol, acetamide, and            C₁-C₃ alkyl).

In some embodiments, R^(x) is:

-   -   wherein:        -   each R^(1c) is independently substituted or unsubstituted            (e.g., straight or branched) alkyl (e.g., substituted with            one or more (alkyl) substituent, each (alkyl) substituent            being independently selected from the group consisting of            carboxylic acid, —SH, thioalkyl, acetamide, amino, oxo,            optionally substituted heterocycloalkyl (e.g., N-attached            pyrrolidinyl substituted with —COOH)) or substituted or            unsubstituted (e.g., straight or branched) heteroalkyl            (e.g., substituted with one or more (heteroalkyl)            substituent, each (heteroalkyl) substituent being            independently selected from the group consisting of            carboxylic acid, amino, thioalkyl, thiol, acetamide, and            C₁-C₃ alkyl).

In some embodiments, each R^(1c) is independently substituted orunsubstituted (e.g., straight or branched) alkyl or substituted orunsubstituted (e.g., straight or branched) heteroalkyl. In someembodiments, each R^(1c) is independently substituted (e.g., straight orbranched) alkyl or substituted (e.g., straight or branched) heteroalkyl.

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) alkyl, the substituted alkyl being substitutedwith one or more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of carboxylic acid,—SH, thioalkyl, acetamide, amino, oxo, and optionally substitutedheterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with —COOH).

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) heteroalkyl, the substituted heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, andC₁-C₃ alkyl.

In some embodiments, R^(1a), R^(1b), and each R^(1c) each independentlycomprise one or more substituent that is a carboxylic acid or an ester.In some embodiments, R^(1a), R^(1b), and each R^(1c) each independentlycomprise one or more substituent that is a carboxylic acid (e.g.,—(C═O)OH). In some embodiments, R^(1a) comprises one or more substituentthat is a carboxylic acid (e.g., —(C═O)OH). In some embodiments, R^(1b)comprises one or more substituent that is a carboxylic acid (e.g.,—(C═O)OH). In some embodiments, each R^(1c) independently comprises oneor more substituent that is a carboxylic acid (e.g., —(C═O)OH). In someembodiments, R^(1a), R^(1b), and each R^(1c) each independently compriseone or more substituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl). Insome embodiments, R^(1a) comprises one or more substituent that is anester (e.g., —(C═O)O—C₁-C₄alkyl). In some embodiments, R^(1b) comprisesone or more substituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl). Insome embodiments, each R^(1c) independently comprises one or moresubstituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl).

In some embodiments, the —(C═O)OH of R^(1a), R^(1b), and/or R^(1c) isoptionally esterified (e.g., —(C═O)OH or —(C═O)O—C₁-C₄alkyl). In someembodiments, the C₁-C₄alkyl is methyl, ethyl, propyl, isopropyl, butyl,or t-butyl.

Provided in some embodiments herein is a compound having the structureof Formula (Ic):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof,

wherein:

-   -   L is bond, —(C═O)(OCR⁸R⁹)—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;        -   z is 1-6;    -   X is absent or —O—; and    -   R^(y) is:

-   -   -   each R^(4a) and R^(4b) is independently H, halogen, or            substituted or unsubstituted alkyl;        -   p is an integer from 1-10; and        -   q is an integer from 1-3.

In some embodiments, q is 1.

In some embodiments, p is an integer from 3-5. In some embodiments, p is4. In some embodiments, q is 1 and p is 4.

In some embodiments, q is 1 and p is an integer from 3-5.

In some embodiments, each R^(4a) and R^(4b) is independently H orsubstituted or unsubstituted alkyl.

In some embodiments, each R^(4a) and R^(4b) is independently H, halogen,C₁-C₃alkyl, or C₁-C₃haloalkyl. In some embodiments, each R^(4a) andR^(4b) is H.

In some embodiments, R^(y) is:

In some embodiments, the sulfoxide of any compound provided herein isracemic. In some embodiments, the sulfoxide of any compound providedherein is an enantiomer. In some embodiments, the sulfoxide of anycompound provided herein is has a stereochemistry that is (R) or (S).

In some embodiments, provided herein is a compound having the structureof Formula (Id):

or a pharmaceutically acceptable salt or solvate (e.g., or astereoisomer) thereof,

wherein:

-   -   L is bond, —(C═O)(OCR⁸R⁹)_(z)—, or —(C═O)(OCR⁸R⁹)_(z)O—;        -   each R⁸ and R⁹ is independently H, halogen, C₁-C₃-alkyl,            C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or R⁸ and            R⁹ are taken together with the atoms to which they are            attached to form a C₃-C₅-cycloalkyl;    -   z is 1-6;    -   X is absent or —O—; and    -   R² is:

-   -   -   R⁵ is —SR^(1c);            -   R^(1c) is substituted or unsubstituted (e.g., straight                or branched) alkyl (e.g., substituted with one or more                (alkyl) substituent, each (alkyl) substituent being                independently selected from the group consisting of                carboxylic acid, —SH, thioalkyl, acetamide, amino, oxo,                optionally substituted heterocycloalkyl (e.g.,                N-attached pyrrolidinyl substituted with —COOH)) or                substituted or unsubstituted (e.g., straight or                branched) heteroalkyl (e.g., substituted with one or                more (heteroalkyl) substituent, each (heteroalkyl)                substituent being independently selected from the group                consisting of carboxylic acid, amino, thioalkyl, thiol,                acetamide, and C₁-C₃ alkyl);        -   R⁶ and R⁷ are each independently H, substituted or            unsubstituted alkyl, or substituted or unsubstituted            heteroalkyl;

    -   each R¹⁰ and R¹¹ is independently H, halogen, C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₃-C₅-cycloalkyl, or two of R¹⁰        and R¹¹ are taken together with the atoms to which they are        attached to form a C₃-C₅-cycloalkyl; and        -   s is an integer from 1-10.

In some embodiments, R⁶ and R⁷ are each independently H or substitutedor unsubstituted alkyl (e.g., C₁-C₃ alkyl optionally substituted withoxo). In some embodiments, R⁶ and R⁷ are each independently H or C₁-C₃alkyl optionally substituted with oxo. In some embodiments, R¹ and R⁷are each independently H or —(C═O)CH₃. In some embodiments, R⁶ is H andR⁷ is H or —(C═O)CH₃. In some embodiments, R⁶ is H and R⁷ is —(C═O)CH₃.In some embodiments, R¹ and R⁷ are H.

In some embodiments, each R¹⁰ and R¹¹ is independently H, halogen,C₁-C₃alkyl, or C₁-C₃haloalkyl.

In some embodiments, each R¹⁰ and R¹¹ is H.

In some embodiments, s is 1-3. In some embodiments, s is 1. In someembodiments, s is 1 and R¹⁰ and R¹¹ are H.

In some embodiments, R⁶, R⁷, R¹⁰ and R¹¹ are each H, and s is 1-3.

In some embodiments R^(1c) is substituted alkyl or substitutedheteroalkyl.

In some embodiments, R^(1c) is heteroalkyl substituted with carboxylicacid.

In some embodiments, R^(1c) is alkyl substituted with one or more alkylsubstituent, each alkyl substituent being independently selected fromthe group consisting of carboxylic acid and acetamide.

In some embodiments R^(1c) is substituted heteroalkyl, the heteroalkylbeing substituted with one or more heteroalkyl substituent, eachheteroalkyl substituent being independently selected from the groupconsisting of oxo, carboxylic acid, amino, thioalkyl, thiol, acetamide,and C₁-C₃ alkyl. In some embodiments, R^(1c) is heteroalkyl substitutedwith carboxylic acid.

In some embodiments, R^(1c) is substituted heteroalkyl, the heteroalkylbeing substituted with —COOH and oxo. In some embodiments, R^(1c) issubstituted heteroalkyl, the heteroalkyl being substituted with oxo andacetamide. In some embodiments, R^(1c) is substituted heteroalkyl, theheteroalkyl being substituted with C₁-C₃ alkyl, oxo, and substitutedN-attached heterocycloalkyl. In some embodiments, R^(1c) is substitutedheteroalkyl, the heteroalkyl being substituted with —COOH, C₁-C₃ alkyl,oxo, and thiol.

In some embodiments, R⁵ comprises a radical of one or more keratolyticgroup (e.g., each radical of the one or more keratolytic group beingindependently selected from the group consisting of a radical ofglycolic acid (GA), a radical of thioglycolic acid (TGA), a radical oflactic acid (Lac), a radical of thiolactic acid (TLac), a radical oflipoic acid (Up), a radical of lipoic acid sulfoxide (Lipox), a radicalof dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine (NAC), aradical of cysteine (Cys), a radical of glutathione (GSH), a radical ofcaptopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R⁵ is a radical of one or more keratolytic group,each radical of the one or more keratolytic group being independentlyselected from the group consisting of a radical of glycolic acid (GA), aradical of thioglycolic acid (TGA), a radical of lactic acid (Lac), aradical of thiolactic acid (TLac), a radical of lipoic acid (Lip), aradical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoicacid (diHLip), a radical of N-acetyl cysteine (NAC), a radical ofcysteine (Cys), a radical of glutathione (GSH), a radical of captopril(Cap), and a radical of bucillamine (Buc).

In some embodiments, R⁵ comprises a (thiol) radical of one or morekeratolytic group, each (thiol) radical of the one or more keratolyticgroup being independently selected from the group consisting of a(thiol) radical of thioglycolic acid (TGA), a (thiol) radical ofthiolactic acid (TLac), a (thiol) radical of dihydrolipoic acid(diHLip), a (thiol) radical of N-acetyl cysteine (NAC), a (thiol)radical of cysteine (Cys), a (thiol) radical of glutathione (GSH), a(thiol) radical of captopril (Cap), and a (thiol) radical of bucillamine(Buc).

In some embodiments R⁵ is a thiol radical of one or more keratolyticgroup, each thiol radical of the one or more keratolytic group beingindependently selected from the group consisting of a thiol radical ofthioglycolic acid (TGA), a thiol radical of thiolactic acid (TLac), athiol radical of dihydrolipoic acid (diHLip), a thiol radical ofN-acetyl cysteine (NAC), a thiol radical of cysteine (Cys), a thiolradical of glutathione (GSH), a thiol radical of captopril (Cap), and athiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agentcomprises a (e.g., thiol) radical of one or more keratolytic group, each(e.g., thiol) radical of the one or more keratolytic group beingindependently selected from the group consisting of [Lac-Lac]•,[Lac-NAC]•, [Cys-Cys]•, [diHLip-NAC-NAC]•, [diHLip-NAC]•,[diHLip-Cap-Cap]•, [diHLip-Cap]•, [diHLip-Cys-Cys]•, [diHLip-Cys]•,[diHLip-Lipox-Lipox]•, and [diHLip-Lipox]•.

In some embodiments, the thiol radical of the keratolytic group is thepoint of attachment of R⁵ to the rest of the molecule. In someembodiments, R⁵ attaches to the rest of the molecule to form a disulfidebond.

In some embodiments, R⁵ is:

In some embodiments, R² is:

In some embodiments, R⁷ is H or —(C═O)CH₃. In some embodiments, R⁷ is H.In some embodiments, R⁷ is —(C═O)CH₃.

In some embodiments, each R^(1c) is independently substituted orunsubstituted (e.g., straight or branched) alkyl or substituted orunsubstituted (e.g., straight or branched) heteroalkyl. In someembodiments, each R^(1c) is independently substituted (e.g., straight orbranched) alkyl or substituted (e.g., straight or branched) heteroalkyl.

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) alkyl, the substituted alkyl being substitutedwith one or more (alkyl) substituent, each (alkyl) substituent beingindependently selected from the group consisting of carboxylic acid,—SH, thioalkyl, acetamide, amino, oxo, and optionally substitutedheterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with —COOH).

In some embodiments, each R^(1c) is independently substituted (e.g.,straight or branched) heteroalkyl, the substituted heteroalkyl beingsubstituted with one or more (heteroalkyl) substituent, each(heteroalkyl) substituent being independently selected from the groupconsisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, andC₁-C₃ alkyl.

In some embodiments, R⁵ and each R^(1c) each independently comprise oneor more substituent that is a carboxylic acid or an ester. In someembodiments, R⁵ and each R^(1c) each independently comprise one or moresubstituent that is a carboxylic acid (e.g., —(C═O)OH). In someembodiments, R⁵ and each R^(1c) each independently comprise one or moresubstituent that is an ester (e.g., —(C═O)O—C₁-C₄alkyl).

In some embodiments, the —(C═O)OH of R⁵ and/or R^(1c) is optionallyesterified (e.g., —(C═O)OH or —(C═O)O—C₁-C₄alkyl). In some embodiments,the C₁-C₄alkyl is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

Provided in some embodiments herein is a compound, a stereoisomerthereof, or a pharmaceutically acceptable salt of the compound or thestereoisomer, having a structure provided in Table 1.

TABLE 1

Compound R X L 1

absent bond 2

absent bond 3

absent bond 4

absent bond 5

absent bond 6

absent bond 7

absent bond 8

absent bond 9

absent bond 10

absent bond 11

absent bond 12

absent bond 13

absent bond 14

absent bond 15

absent bond 16

absent bond 17

absent bond 18

absent bond 19

absent bond 20

absent —(C═O)OCH(CH₃)O— 21

absent —(C═O)OCH₂O— 22

absent —(C═O)OCH(CH₃)O— 23

absent —(C═O)OCH(CH₃)O— 24

—O— —(C═O)OCH₂O— 25

—O— (C═O)OCH(CH₂CH₃)O— 26

absent —(C═O)OC(CH₃)₂O— 27

absent bond 28

absent bond 29

absent bond 30

absent bond 31

absent bond 32

absent bond 33

absent bond 34

absent bond 35

absent bond 36

absent —(C═O)(O(CH₂)₂)₄O— 37

absent —(C═O)(O(CH₂)₂)₈O— 38

absent bond 39

absent bond 40

absent bond 41

absent bond 42

absent bond 43

absent bond 44

absent bond 45

absent bond 46

absent bond 47

absent bond 48

absent bond 49

absent bond 50

absent bond 51

absent bond

Each recitation of

provided herein, unless otherwise stated, includes a specific andexplicit recitation of:

The compounds used in the reactions described herein are made accordingto organic synthesis techniques starting from commercially availablechemicals and/or from compounds described in the chemical literature orthe present disclosure. “Commercially available chemicals” are obtainedfrom standard commercial sources including Acros Organics (Pittsburgh,Pa.), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical andFluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research(Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.),Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge,N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester,N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals(Leicestershire, UK), Frontier Scientific (Logan, Utah), ICNBiomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.),Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc.(Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co.(Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.),Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA,Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandier et al., “Organic Functional Group Preparations,”2^(nd) Ed., Academic Press, New York, 1983; H. O. House, “ModernSynthetic Reactions”, 2^(nd) Ed., W. A. Benjamin, Inc. Menlo Park,Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2^(nd) Ed., JohnWiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry:Reactions, Mechanisms and Structure”, 40 Ed., Wiley-Interscience, NewYork, 1992. Additional suitable reference books and treatise that detailthe synthesis of reactants useful in the preparation of compoundsdescribed herein, or provide references to articles that describe thepreparation, include for example, Fuhrhop, J. and Penzlin G. “OrganicSynthesis: Concepts, Methods, Starting Materials”, Second, Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman,R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford UniversityPress, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations” 2^(nd)Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure” 4^(th) Edition(1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor)“Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-2987 I-1;Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups”(1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “OrganicChemistry” 7^(th) Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0;Stowell, J. C., “Intermediate Organic Chemistry” 2^(nd) Edition (1993)Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals:Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999)John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “OrganicReactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and“Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through theindices of chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsnot commercially available in catalogs are optionally prepared by customchemical synthesis houses, where many of the standard chemical supplyhouses (e.g., those listed above) provide custom synthesis services. Areference for the preparation and selection of pharmaceutical salts ofthe keratolytic conjugate described herein is P. H. Stahl & C. G.Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica ChimicaActa, Zurich, 2002.

In some embodiments, a compound provided herein is a compoundrepresented by any one of Formula (I), Formula (I-A), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), or Table 1. In someembodiments, a compound provided herein is administered as a purechemical. In other embodiments, a compound provided herein is combinedwith a pharmaceutically suitable or acceptable carrier (also referred toherein as a pharmaceutically suitable (or acceptable) excipient,physiologically suitable (or acceptable) excipient, or physiologicallysuitable (or acceptable) carrier) selected on the basis of a chosenroute of administration and standard pharmaceutical practice asdescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Provided in some embodiments herein is a pharmaceutical compositioncomprising at least one keratolytic conjugate together with one or morepharmaceutically acceptable carriers. The carrier(s) (or excipient(s))is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

In some embodiments, a compound provided herein (e.g., such as acompound represented by any one of Formula (I), Formula (I-A), Formula(Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1) issubstantially pure, in that it contains less than, for example, about5%, or less than about 1%, or less than about 0.1%, of other organicsmall molecules, such as unreacted intermediates or synthesisby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa.

(2005)).

In some embodiments provided herein is a pharmaceutical compositioncomprising a compound provided herein (e.g., such as a compoundrepresented by any one of Formula (I), Formula (I-A), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), or Table 1) and at least onepharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition is suitable for ophthalmic administration. Insome embodiments, the pharmaceutical composition is suitable for topicalophthalmic administration. In some embodiments, topical ophthalmicadministration is administration in and/or around the eye, such as tothe eyelid margin. In some embodiments, topical ophthalmicadministration is administration to the ocular surface and the innersurface to the eyelid.

In some embodiments, a keratolytic conjugate provided herein (such as acompound represented by any one of Formula (I), Formula (I-A), Formula(Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1) isformulated as a solution or suspension for topical administration to theeye.

In some embodiments, a keratolytic conjugate provided herein (such as acompound represented by any one of Formula (I), Formula (I-A), Formula(Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1) isformulated for administration by injection. In some instances, theinjection formulation is an aqueous formulation. In some instances, theinjection formulation is a non-aqueous formulation. In some instances,the injection formulation is an oil-based formulation, such as sesameoil, or the like.

In some embodiments, the dose of the composition comprising at least onekeratolytic conjugate as provided herein differ, depending upon thepatient's (e.g., human) condition, that is, general health status, age,and other factors.

Pharmaceutical compositions provided in some embodiments herein areadministered in a manner appropriate to the disease to be treated (orprevented). An appropriate dose and a suitable duration and frequency ofadministration will be determined by such factors as the condition ofthe patient, the type and severity of the patient's disease, theparticular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity). Optimal doses are generally determined using experimentalmodels and/or clinical trials. The optimal dose depends upon the bodymass, weight, or blood volume of the patient.

In other embodiments, the topical compositions described herein arecombined with a pharmaceutically suitable or acceptable carrier (e.g., apharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (or acceptable) excipient, or physiologically suitable (oracceptable) carrier). Exemplary excipients are described, for example,in Remington: The Science and Practice of Pharmacy (Gennaro, 21n Ed.Mack Pub. Co., Easton, Pa. (2005)).

Methods of Treatment Utilizing Keratolytic Conjugates

In some embodiments provided herein is a method of treating adermatological or ophthalmic disease or disorder in a patient in need ofthereof, comprising administering to the patient any compound providedherein, or a pharmaceutically acceptable salt thereof, or a (e.g.,pharmaceutical) composition comprising any compound provided herein, ora pharmaceutically acceptable salt thereof, such as a compoundrepresented by any one of Formula (I), Formula (I-A), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), or Table 1. In someembodiments provided herein the pharmaceutical composition is in theform of a solution or suspension suitable for topical ophthalmicadministration. In some embodiments, topical ophthalmic administrationis administration in and/or around the eye, such as to the eyelidmargin. In some embodiments, topical ophthalmic administration isadministration to the ocular surface and the inner surface to theeyelid.

In some embodiments, the dermatological or ophthalmic disease ordisorder is inflammation or hyperkeratosis (e.g., of the eyes or skin).In some embodiments, the dermatological or ophthalmic disease ordisorder is inflammation or hyperkeratosis of the eyes or skin (e.g.,the ocular surface). In some embodiments, the dermatological orophthalmic dermatological disease or disorder is selected from the groupconsisting of meibomian gland dysfunction (MGD), dry eye disease (DED),ocular manifestations of graft versus host disease, vernalkeratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de LangeSyndrome, evaporative eye disease, aqueous deficiency dry eye,blepharitis, and seborrheic blepharitis. In some embodiments, thedermatological or ophthalmic disease or disorder is inflammation orhyperkeratosis (e.g., of the eyes or skin), such as, for example,meibomian gland dysfunction (MGD), dry eye disease (DED), ocularmanifestations of graft versus host disease, vernalkeratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de LangeSyndrome, evaporative eye disease, aqueous deficiency dry eye,blepharitis, seborrheic blepharitis, or any combination thereof.

In some embodiments, the ophthalmic disease or disorder is selected fromthe group consisting of dry eye, lid wiper epitheliopathy (LWE), contactlens discomfort (CLD), dry eye syndrome, evaporative dry eye syndrome,aqueous deficiency dry eye syndrome, blepharitis, keratitis, meibomiangland dysfunction, conjunctivitis, lacrimal gland disorder, contact lensrelated conditions and inflammation of the anterior surface of the eye,infection of the anterior surface of the eye, and autoimmune disorder ofthe anterior surface of the eye.

Provided herein is a method for treating an ocular surface disorder inan individual in need thereof comprising topical administration of akeratolytic conjugate to the individual in need thereof. In someembodiments, administration occurs with the assistance of a health-careprovider (e.g., this category includes both acute and maintenance usesof the keratolytic conjugate). An acute use, in some embodiments,requires a stronger keratolytic conjugate (either in terms ofconcentration of the agent or the inherent activity of the agent). Amaintenance use, in some embodiments, allows for the use of lowerconcentrations of the agent, or agents with lower inherent activity. Amaintenance use, in some embodiments, involves a patient at a routinevisit to the health care provider. Both acute uses and maintenance usesoptionally involve use of an eye-protecting device or apparatus. In someembodiments, the acute use is performed by the health care provider, andthe maintenance use is performed by the patient or non-health careprovider. In some embodiments, administration does not occur with theactive assistance of a health care provider (e.g., but rather involvesthe patient applying the keratolytic conjugate to his/her own eyelidmargin). In some embodiments, such administration occurs over anextended period of time (e.g., one way of describing thispatient-administered multi-administration mode is as a chronic use). Insome embodiments, different or second formulations of the keratolyticconjugate are used for chronic or patient-administered uses. In someembodiments the different or second formulation utilizes a lowerconcentration of the keratolytic conjugate. In some embodiments, thesecond or different formulation utilizes a keratolytic conjugate thathas a lower activity than the first formulation.

It should be understood that the present methods also include thephysical removal of an obstruction in an meibomian gland (e.g., followedby chronic and/or maintenance administration of a keratolytic conjugateprovided herein).

In some embodiments provided herein is a method for treating meibomiangland dysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier results in enhanced meibumproduction.

In some embodiments, the topical administration of the compositioncomprising a therapeutically-effective amount of at least onekeratolytic conjugate in an ophthalmically-acceptable carrier occursuntil the keratinized obstruction is relieved. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier occurs periodically afterrelieving of the keratinized obstruction. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a single administration. Insome embodiments, the topical administration of the compositioncomprising a therapeutically-effective amount of at least onekeratolytic conjugate in an ophthalmically-acceptable carrier is aperiodic administration. In some embodiments, the topical administrationof the composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs once a day. In some embodiments, the topical administration ofthe composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs twice a day. In some embodiments, the topical administration ofthe composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs more than twice a day.

In some embodiments, the composition for topical administrationcomprises a therapeutically-effective amount of at least one keratolyticconjugate in an ophthalmically-acceptable carrier is a solution. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a solution suitable fortopical administration as eye drops. In some embodiments, thecomposition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a gel, ocular insert, spray,or other topical ocular delivery method. In some embodiments, thecomposition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a semi-solid. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is homogenous. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a dispersion. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is hydrophilic. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier and an oleaginous base. In someembodiments, the composition for topical administration comprises atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier and at least oneophthalmically-acceptable excipient.

In some embodiments provided herein is a method for treating MGD in apatient in need thereof comprising topical administration of acomposition comprising a keratolytic conjugate. In some embodiments, thetopical administration of the composition comprising a keratolyticconjugate occurs once a week. In some embodiments, the topicaladministration of the composition comprising a keratolytic conjugateoccurs twice a week. In some embodiments, the topical administration ofthe composition comprising a keratolytic conjugate occurs every otherday. In some embodiments, the topical administration of the compositioncomprises a keratolytic conjugate occurs every day. In some embodiments,the topical administration of the composition comprises a keratolyticconjugate occurs several times a day.

In some embodiments, the method comprises administering a compound orformulation provided herein in an acute treatment scenario. In someembodiments, the method comprises treatment of a patient naïve totreatment. In some embodiments, the method comprises administering acompound or formulation provided herein in a chronic treatment scenario.In some embodiments, the method comprises administering a compound orformulation provided herein in a maintenance therapy scenario. In anacute treatment scenario, the administered dosage of keratolyticconjugate may be higher than the administered dosage of keratolyticconjugate employed in a chronic treatment scenario or a maintenancetherapy scenario. In an acute treatment scenario, the keratolyticconjugate may be different from the keratolytic conjugate employed in achronic treatment scenario. In some embodiments, the course of therapybegins in the initial phase of therapy as an acute treatment scenarioand later transitions into a chronic treatment scenario or a maintenancetherapy scenario. In some embodiments, the meibomian gland openingpharmacological agent administered in the acute treatment scenario is akeratolytic agent and/or keratoplastic agent, and the pharmacologicalagent administered in the chronic treatment scenario or a maintenancetherapy scenario is a keratolytic conjugate.

In some embodiments, an initial treatment is administered (e.g., by aphysician or healthcare professional) to an individual to initially opena blockage of the meibomian gland, such as by placing a more highlyconcentrated formulation of one of the keratolytic conjugate providedherein. In the event the higher concentration formulations are required,the application thereof may require ocular shielding or other activityto minimize the impact of irritation or disruption of the ocular surfaceor surrounding tissues. Following such a procedure, a patient may begiven a different formulation of keratolytic conjugate to take home toapply periodically to the lid margin to maintain the patency of themeibomian gland. Such application may occur twice daily, once a day,weekly or monthly, depending on the formulation activity and thetherapeutic product profile of the formulation.

Provided in some embodiments of the methods of treatment describedherein is the location of the topical administration of the composition.In some embodiments, the composition comprising a keratolytic conjugateis administered such that no irritation to eye occurs. In someembodiments, the composition comprising a keratolytic conjugate isadministered to the eye lid margin.

In some embodiments of the methods of treatment provided herein is theuse of a protective element provided to the eye to avoid irritation tothe eye. Although the formulations described herein are generallynon-irritating, in some embodiments (e.g., high concentration of agentor when used on a sensitive eye) a protective element provides anadditional layer of safety and comfort for the patient. In someembodiments, the composition comprising a keratolytic conjugate isadministered while an eye shield is placed on the eye to reduce contactof the pharmacological agent with the cornea and/or conjunctiva suchthat reduced irritation to eye occurs. In some embodiments, the eyeshield is a contact lens or an eye covering. In some embodiments, theeye covering comprises a self-adhesive. In some embodiments, thecomposition comprising a keratolytic conjugate is administered while thelid is pulled away from the globe to reduce contact of thepharmacological agent with the cornea and/or conjunctiva such thatreduced irritation to eye occurs.

While exemplary embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

EXAMPLES I. Chemical Synthesis

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Startingmaterials were purchased from commercial sources or synthesizedaccording to the methods described herein or using literature proceduresor the present disclosure.

Abbreviations

The following abbreviations are used in the Examples and other parts ofthe description:

AcOH: Acetic acid

CDCl₃: Deuterochloroform

COMU:(1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate

CV: Column Volume DBU: 1,8-Diazabicyclo[5,4,0]undec-7-ene DCM:Dichloromethane DIPEA: N,N-Diisopropylethylamine

D₂O: Deuterium oxide

DMF: N,N-Dimethylformamide

DMSO-D6: Deuterated dimethyl sulfoxideDPBS: Dulbecco's phosphate-buffered salineEtOAc: Ethyl acetate

h: Hour(s)

HCl: Hydrochloric acidLCMS: Liquid chromatography-mass spectrometry

M: Molar MeCN; Acetonitrile MeOH: Methanol

MgSO₄: Magnesium sulfatemins: Minute(s)

N₂: Nitrogen

Na₂SO₄: Sodium sulfateNH₄Cl: ammonium chlorider.t.: Room temperatureRt: Retention time

s: Second sat.: Saturated TEA: Triethylamine THF: Tetrahydrofuran vac:Vacuum Analytical Methods:

Method A: Waters Sunfire C18 3.5 μm, 50×4.6 mm; A=water+0.1% formicacid; B=MeCN; 45° C.; % B: 0.0 min 5% 2.25 ml/min, 1.0 min 37.5% 2.2ml/min, 3.0 min 95% 2.2 ml/min, 3.5 min 95% 2.3 ml/min, 3.51 min 0% 2.3mL/min, 4.0 min 0% 2.25 mL/min.

Method B: Waters Sunfire C18 5 μm, 100×4.6 mm; A=water+0.1% formic acid;B=MeCN+0.1% formic acid; 45°; % B: 0.0 min 5%, 0.50 min 5%, 7.5 min 95%,10.0 min 95%, 10.1 min 5%, 13.0 min 5%; 1.5 mL/min.

Method C: Phenomenex Luna C18 (2) 3 μm, 50×4.6 mm; A=water+0.1% formicacid; B=MeOH+0.1% formic acid; 45°; % B: 0.0 min 5% 2.25 mL/min, 1.0 min37.5% 2.2 mL/min, 3.0 min 95% 2.2 ml/min, 3.5 min 95% 2.3 mL/min, 3.51min 5% 2.3 mL/min, 4.0 min 5% 2.25 ml/min.

Method D: Waters Sunfire C18 3.5 μm, 50×4.6 mm; A=water+0.1% formicacid; B=MeCN; 45° C.; % B: 0.0 min 5% 2.25 mL/min, 1.0 min 20% 2.2ml/min, 3.0 min 50% 2.2 mL/min, 3.25 min 95% 2.2 mL/min, 3.50 min 95%2.3 mL/min, 3.51 min 100% 2.30 mL/min, 4.0 min 100% 2.25 mL/min.

Method E: Phenomenex Gemini NX C18 5 μm, 150×4.6 mm; A=water+0.1% formicacid; B=MeOH; 40° C.; % B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min95%, 10.1 min 5%, 13.0 min 5%; 1.5 ml/min.

Method F: Waters CSH C18 1.7 μm, 100×2.1 mm; A=water+0.1% formic acid;B=MeCN; 45° C.; % B: 0.05 min 5% 0.35 mL/min, 5.00 min 95% 0.35 ml/min,6.60 min 5% 0.35 ml/min. 8.00 min end.

Chemical Synthesis Example 1 Method 1: Step 1: Methyl2-((tert-butyldiphenylsilyl)oxy)acetate

To a stirred solution of methyl glycolate (0.77 mL, 10.0 mmol) inanhydrous DMF (14 ml) were added imidazole (803 mg, 11.8 mmol) andtert-butylchlorodiphenylsilane (3.12 mL, 12.0 mmol) and the mixturestirred at room temperature for 3 hours. The solvent was evaporated invacuo and the residue diluted with DCM and washed with ice-cold water.The organic layer was dried (MgSO₄) and the solvent evaporated in vacuoto give the crude product which was purified by flash chromatography(Biotage SP1; 100 g SNAP cartridge) eluting with isohexane→10%EtOAc-isohexane to yield the title compound as a colourless oil (3.26 g,99%). LCMS (Method A): Rt=3.50 min; [M+Na]+=351.2. ¹H-NMR (400 MHz,CDCl₃) δ 7.67-7.69 (m, 4H), 7.37-7.43 (m, 6H), 4.24 (s, 2H), 3.68 (s,3H), 1.09 (t, J=3.0 Hz, 9H)

Step 2: 2-((tert-Butyldiphenylsilyl)oxy)acetic acid

To a stirred solution of methyl 2-((tert-butyldiphenylsilyl)oxy) (1.00g, 3.04 mmol) in THF (2.75 mL) and water (0.92 ml) was added 0.75 Mlithium hydroxide_((aq))(4.06 mL, 3.05 mmol) and the mixture stirred atroom temperature for 20 hours. The reaction mixture was diluted withwater (10 mL) and extracted with Et₂O (3×20 mL). The aqueous phase wasacidified to pH3 with 5 M HCl_((aq)), and the solution extracted withEtOAc (3×20 mL). The combined organics were dried (MgSO₄), filtered andthe solvent evaporated in vacuo. The crude product was purified by flashchromatography (Biotage SP1; 25 g SNAP cartridge) eluting withisohexane→EtOAc to yield the title compound as a colourless oil (0.65 g,68%). LCMS (Method A): Rt=2.77 mis; [M−H]−=313.3. ¹H-NMR (400 MHz,CDCl₃) δ 7.61-7.66 (m, 4H), 7.39-7.47 (m, 6H), 4.22 (s, 2H), 1.08-1.12(m, 9H)

Step 3:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-((tert-butyldiphenylsilyl)oxy)acetate

To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (97 mg,0.308 mmol) and azithromycin dihydrate (291 mg, 0.370 mmol) in toluene(15 mL) at room temperature was added TEA (155 μL, 1.11 mmol),4-(dimethylamino)pyridine (286 mg, 2.34 mmol) and 2,4,6-trichlorobenzoylchloride (162 μL, 1.05 mmol). The mixture was stirred at roomtemperature for 121 hours. The resulting mixture was diluted with DCM(10 mL), sat. NaHCO_(3(aq)) (10 mL) and H₂O (10 mL) and the layersseparated. The aqueous phase was extracted with DCM (3×10 mL). Thecombined organics were dried (MgSO₄), filtered, and the solventevaporated in vacuo. The crude product was purified by flashchromatography (Biotage SP1; 10 g SNAP cartridge) eluting with 4:1isohexane-acetone (1% TEA)→acetone (1% TEA) and further purified byflash chromatography (Biotage SP1; 10 g SNAP cartridge) eluting withisohexane→acetone (1% TEA). The crude product was then purified byreversed-phase preparative HPLC. Fractions containing product werecombined, diluted with DCM and neutralised with sat. NaHCO_(3(aq)). Theorganic layer was separated and the aqueous phase extracted with DCM.The combined organics were washed with sat. brine solution, dried(MgSO₄) and evaporated in vacuo to yield the title compound as acolourless gum (40 mg, 12%). LCMS (Method A): Rt=1.72 min; [M+H]+=1046.0

Step 4:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-hydroxyacetate

To a stirred solution of(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-((tert-butyldiphenylsilyl)oxy)acetate (40 mg, 0.0383 mmol) inanhydrous THF (1 mL) under N₂ was added 1 M tetrabutylammonium fluoridehydrate (115 μL, 0.115 mmol) in THF. The reaction was stirred at roomtemperature for 2 hours then quenched with sat. NaHCO_(3(aq)) andextracted with EtOAc. The organic layer was washed with sat. brinesolution and the layers separated. The organic phase was dried (MgSO₄),filtered and the solvent evaporated in vacuo. The crude product waspurified by flash chromatography (Biotage SP1; 10 g SNAP cartridge)eluting with isohexane (2% TEA)→acetone (2% TEA) to yield the titlecompound as a white solid (12 mg, 39%). LCMS (Method B): Rt=3.04 min;[M+H]+=807.9.

Method 2:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxo-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-hydroxypropanoate

This reaction was performed using a flow setup: A solution ofL-(+)-lactic acid (0.24 mL, 3.18 mmol) and DIPEA (0.67 mL, 3.82 mmol) inDCM (10 mL) (flow rate: 2.0 mL/min) and a solution of triphosgene (0.15g, 0.510 mmol) in DCM (6 mL) (flow rate: 1.2 mL/min) were introduced toa T-shape mixer 1 at r.t. with syringe pumps. The resultant mixture waspassed through reaction tube 1 (inner diameter: 0.8 mm, length: 54 mm,volume: 27 mL, reaction time: 0.5 s) at r.t. The resultant mixture and asolution of azithromycin dihydrate (1.00 g, 1.27 mmol) in DCM (10 mL)(flow rate: 2.0 mL/min) were introduced to T- shape mixer 2 at r.t. Theresultant mixture was passed through reaction tube 2 (inner diameter:0.8 mm, length: 742 mm, volume: 373 μL, reaction time: 4.3 s) at r.t.After 55 s the resultant mixture was collected, diluted with DCM (25mL), and washed with sat. NH₄Cl_((aq)) (8×30 mL). The combined organicswere washed with sat. brine solution (20 mL), dried (MgSO₄), filteredand the solvent evaporated in vacuo. The crude product was purified byflash chromatography (Biotage SP1; 25 g Sfar cartridge) eluting with 8:2isohexane-acetone (1% TEA)→acetone (1% TEA) to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-hydroxypropanoate (227 mg, 22%) as a white solid. LCMS (Method D):Rt=1.73 mins; [M+H]+=821.6.

Chemical Synthesis Example 2 Method A:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate

(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((R)-1,2-dithiolan-3-yl)pentanoate (1.50 g, 1.60 mmol) had been storedin vacuo at 30° C. in the dark (vac oven) for a period of 2 weeks. Overthis time approximately 10% of the various sulfoxide isomers had formed.The crude material was purified by flash chromatography (Biotage SP1; 25g SNAP cartridge) eluting with isohexane+3:1 isohexane-acetone (1%TEA)→acetone to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate (103 mg, 3%) as a whitesolid. LCMS (Method A): Rt=1.60 mins; [M+H]+=953.7.

Method B:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate

A mixture of 5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoic acid and5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoic acid (0.73 g, 3.27 mmol),azithromycin (1.87 g, 2.50 mmol), and1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (3.74 g, 8.74 mmol) were dissolved in anhydrous DCM(25 mL). DIPEA (2.5 mL, 14.3 mmol) was added and the mixture stirred at30° C. for 20 h. The mixture was diluted with DCM (40 mL) and thesolution washed successively with sat. NH₄C_((aq))(2×60 mL) and sat.brine solution (50 mL). The organic phase was dried (MgSO₄), filteredand the solvent evaporated in vacuo. The crude product was purified byflash chromatography eluting with isohexane (1% TEA)→3:1isohexane-acetone (1% TEA) to yield the title mixture (1.45 g, 58%) as aviscous orange oil. LCMS (Method A): R_(t)=2.14 min; [M+H]⁺=953.6.

Chemical Synthesis Example 3 Step 1:(R)-2,2-Dimethylthiazolidine-4-carboxylic acid

A suspension of L-cysteine (2.00 g, 16.0 mmol) in anhydrous acetone (50mL) was stirred at reflux under an atmosphere of nitrogen for 18 hours.The reaction mixture was cooled to r.t., filtered through a celitecartridge, concentrated to ^(˜)50% of its original volume then left tostand at r.t. After 4 hours the mother liquor was decanted. The solidwas further washed with acetone (10 mL) then dried in vacuo to yield(R)-2,2-dimethylthiazolidine-4-carboxylic acid (2.29 g, 89%) as a whitesolid. LCMS (Method A): Rt=0.53 mins; [M+H]⁺=162.1. ¹H-NMR (400 MHz,D₂O) δ 4.47 (dd, J=8.0, 7.3 Hz, 1H), 3.50 (dd, J=12.1, 8.0 Hz, 1H), 3.35(dd, J=12.4, 7.3 Hz, 1H), 1.70 (s, 3H), 1.69 (3s, 3H).

Step 2: (R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid

(R)-2,2-Dimethylthiazolidine-4-carboxylic acid (500 mg, 3.10 mmol) wasdissolved in acetone (30 mL). Acetic anhydride (0.60 mL, 6.20 mmol) wasadded in one portion and the mixture stirred at r.t. for 10 minutes. DBU(0.93 mL, 6.20 mmol) was added in one portion. The reaction mixture wasstirred at r.t. for 16 hours. The mixture was diluted with sat.NH₄Cl_((aq)) (50 mL) and EtOAc (30 mL) and the layers separated. Theaqueous phase was extracted with EtOAc (2×30 mL) and the combinedorganics dried (MgSO₄), filtered and the solvent evaporated in vacuo.The aqueous phase was acidified with 2M HCl and the solution extractedwith EtOAc (3×30 mL). The combined organics were dried (MgSO₄), filteredand the solvent evaporated in vacuo.(R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (350 mg, 56%)was obtained as a white solid. LCMS (Method E), Rt=5.70 mins;[M−H]⁻=204.3. ¹H-NMR (400 MHz, acetone-D6) δ 11.52 (br s, 1H), 5.09 (dd,J=6.0, 0.9 Hz, 1H), 3.41 (dd, J=11.9, 6.0 Hz, 1H), 3.30 (dd, J=11.9, 1.4Hz, 1H), 2.02 (s, 3H), 1.83 (s, 3H), 1.79 (s, 3H).

Step 3:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-3-acetyl-2,2-dimethylthiazolidine-4-carboxylate

(R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (100 mg, 0.490mmol), azithromycin (380 mg, 0.490 mmol) and COMU (737 mg, 1.72 mmol)were dissolved in anhydrous THF (10 mL). DIPEA (0.50 mL, 2.95 mmol) wasadded and the mixture stirred at r.t. under N₂ for 18 hours. The mixturewas diluted with EtOAc (50 mL) and the solution washed with satNH₄Cl_((aq)) (3×20 mL), dried (MgSO₄), filtered and the solventevaporated in vacuo. The crude product was purified by flashchromatography (Biotage SP1; 25 g Sfar cartridge) eluting withisohexane→3:1 isohexane-acetone (1% TEA).(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-3-acetyl-2,2-dimethylthiazolidine-4-carboxylate (250 mg, 54%) wasobtained as a white solid. LCMS (Method E), Rt=5.43 mins; [M+H]⁺=934.9.¹H-NMR (400 MHz, CDCl₃) δ 5.07 (d, J=4.8 Hz, 1H), 4.74 (dd, J=10.5, 7.3Hz, 1H), 4.68 (td, J=6.2, 2.4 Hz, 1H), 4.58 (d, J=7.3 Hz, 1H), 4.26 (q,J=2.3 Hz, 1H), 4.11-4.21 (m, 1H), 4.00-4.07 (m, 1H), 3.63-3.70 (m, 2H),3.49-3.54 (m, 1H), 3.30-3.38 (in, 3H), 3.22-3.26 (m, 1H), 3.05 (t, J=9.8Hz, 1H), 2.84 (s, 1H), 2.62-2.79 (m, 2H), 2.48-2.57 (m, 1H), 2.33 (d,J=15.6 Hz, 3H), 2.23-2.29 (m, 1H), 2.20 (d, J=10.1 Hz, 4H), 2.12 (d,J=10.1 Hz, 1H), 1.87-2.06 (m, 6H), 1.85 (d, J=6.9 Hz, 2H), 1.35-1.75 (m,4H), 1.29-1.34 (m, 4H), 1.25 (t, J=5.7 Hz, 4H), 1.21 (d, J=6.9 Hz, 3H),1.13-1.16 (m, 1H), 1.06-1.10 (m, 4H), 0.85-0.94 (in, 6H).

Chemical Synthesis Example 4 Step 1:3-Acetyl-2-methylthiazolidine-4-carboxylic acid

To a solution of 2-methyl-1,3-thiazolidine-4-carboxylic acid (300 mg,2.04 mmol) in anhydrous acetone (30 mL) under an atmosphere of nitrogen,was added acetic anhydride (0.39 mL, 4.08 mmol) followed by DBU (0.61mL, 4.08 mmol). The reaction mixture was stirred at r.t. for 17 hours.Water (30 mL) was added and the mixture stirred for 10 minutes. Themixture was extracted with EtOAc (2×30 ml) and the combined organicswashed with sat. brine solution (30 ml), dried (MgSO₄), filtered and thesolvent evaporated in vacuo to yield3-acetyl-2-methylthiazolidine-4-carboxylic acid (212 mg, 55%) as ayellow oil. LCMS (Method C): Rt 1.27, 1.31 mins; [M+H]+=no obvious massion. ¹H-NMR (400 MHz, CDCl₃) δ 8.48 (br s, 2H), 5.08-5.41 (m, 1H),4.70-4.90 (m, 1H), 3.02-3.49 (m, 2H), 2.00-2.18 (m, 3H), 1.48-1.69 (m,3H).

Step 2:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl3-acetyl-2-methylthiazolidine-4-carboxylate

3-Acetyl-2-methyl-thiazolidine-4-carboxylic acid (50 mg, 0.264 mmol),azithromycin (204 mg, 0.264 mmol) and COMU (396 mg, 0.925 mmol) weredissolved in anhydrous THF (20 mL). DIPEA (0.28 mL, 1.59 mmol) was addedand the mixture stirred at r.t. under N₂ for 18 hours. The mixture wasdiluted with EtOAc (50 ml), washed with sat. NH₄Cl_((aq)) (3×20 mL),dried (MgSO₄), and the crude product purified by flash chromatography(Biotage SP1; 25 g Sfar cartridge) eluting with isohexane→3:1isohexane-acetone (1% TEA) to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl3-acetyl-2-methylthiazolidine-4-carboxylate (104 mg, 43%) as anoff-white solid. LCMS (Method C): Rt=1.96 mins; [M+H]⁺=920.7.

Chemical Synthesis Example 5 Step 1:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate

Azithromycin (1.88 g, 2.50 mmol), COMU (3.75 g, 8.76 mmol) and DIPEA(2.60 mL, 15.0 mmol) were dissolved in anhydrous DCM (50 ml).N-Fmoc-(R)-2-amino-3-(S-tert-butyl)propanoic acid (1.00 g, 2.50 mmol)was added and the mixture stirred at 30° C. for 20 hours. The solutionwas diluted with DCM (10 mL) and the solution washed with sat.NH₄Cl_((aq)) (2×30 mL). The organic phase was dried (MgSO₄), filteredand the solvent evaporated in vacuo. The crude product was purified byflash chromatography (Biotage Isolera four; 50 g Sfar cartridge),eluting with 95:5 isohexane-acetone (1% TEA)→65:35 isohexane-acetone (1%TEA) to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate (1.35g, 45%) as a yellow oil. LCMS (Method A): Rt=2.02 mins; [M+H]⁺=1131.3.

Step 2:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylS-(tert-butyl)-L-cysteinate

(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate (1.35g, 1.19 mmol) was dissolved in DMF (20 mL). Piperidine (5.00 mL, 50.6mmol) was added and the mixture stirred at r.t. for 90 minutes. Thesolvent was evaporated in vacuo and then dried in a vac. oven at 40° C.for 16 hours. Crude(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylS-(tert-butyl)-L-cysteinate (3.14 g) was obtained as a yellow solidwhich was purified no further. LCMS (Method A): R_(t)=1.57 min;[M+H]⁺=909.0.

Step 3:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-(tert-butyl)-L-cysteinate

Crude(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylS-(tert-butyl)-L-cysteinate (1.00 g) was dissolved in anhydrous acetone(18 mL). DBU (0.160 mL, 1.10 mmol) was added in one portion and themixture stirred at r.t. for 10 mins. Acetic anhydride (0.100 mL, 1.10mmol) was added dropwise over 2 mins. The mixture was stirred at r.t.for 18 h. The solvent was evaporated in vacuo and the residue dilutedwith EtOAc (25 mL) and sat. NH₄Cl₁,) (25 mL). The mixture was stirred atr.t. for 10 minutes and the layers separated. The organic phase wasdried (MgSO₄), filtered and the solvent evaporated in vacuo. The crudeproduct was purified by flash chromatography (Biotage Isolera four; 50 gSfar cartridge), eluting with 9:1 isohexane-acetone (1% TEA)+6:4isohexane-acetone (1% TEA) to yield2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-(tert-butyl)-L-cysteinate (650 mg, 56%) as a white solid.LCMS (Method A): Rt=1.60 mins; [M+H]+=950.8.

Step 4:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxo-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate

2-Nitrobenzenesulfenyl chloride (40.5 mg, 0.210 mmol) was suspended inanhydrous acetic acid (4.20 ml) and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-(tert-butyl)-L-cysteinate (200-400 mg, 0.210-0.420 mmol) wasadded. The mixture was stirred at r.t. for 30 mins. The solvent wasevaporated in vacuo to yield crude(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (180-375 mg) as an orangeoil. No purification was attempted. LCMS (Method A): Rt=1.62 mins;[M+H]+=1047.7.

Step 5:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylacetyl-L-cysteinate

Method 1: To a solution of thioglycolic acid (10.0 μL, 0.0900 mmol) inacetone (1 mL) was added crude(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (180 mg, 0.0300 mmol) andDIPEA (10 μL, 0.0573 mmol). The resulting suspension was stirred at r.t.for 1 h. The solvent was evaporated in vacuo. The crude product purifiedby flash chromatography (Biotage Isolera Four; 10 g SNAP cartridge)eluting with 9:1 isohexane-acetone (1% TEA)→6:4 isohexane-acetone (1%TEA) to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylacetyl-L-cysteinate (5.0 mg, 2%) as a yellow solid. LCMS (Method A):Rt=1.53 mins; [M+H]+=894.7.

Method 2: To a solution of thioglycolic acid (82.0 μL, 1.18 mmol) inanhydrous acetone (10 mL) was added(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylN-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (375 mg, 0.358 mmol) andTEA (110 μL, 0.789 mmol). The solvent was evaporated in vacuo and theresultant orange oil purified by reversed-phase preparative HPLC. Toeach fraction containing purified pure target material was immediatelyadded water (10 mL), DCM (10 ml) and potassium acetate (0.300 g) and thelayers separated. The organic phases were dried (Na₂SO₄), filtered, andthe filtrates combined. The solvent was evaporated in vacuo to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylacetyl-L-cysteinate (79 mg, 21%) as a white solid. LCMS (Method A):R_(t)=1.54 min; [M+H]⁺=894.6.

Chemical Synthesis Example 6 Step 1:((R)-2-Methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-proline

Captopril (0.500 g, 2.30 mmol) was dissolved in DCM (8 ml) and4,4′,4″-trimethoxytrityl chloride (0.850 g, 2.30 mmol) added under N₂.TEA (0.430 mL, 3.06 mmol) was added dropwise and the solution stirred atr.t. for 1.5 h. Water (5 ml) was added and the layers separated (phaseseparator). The aqueous phase was diluted with sat. NH₄Cl_((aq)) (15 mL)and extracted with dichloromethane (15 ml). The combined organics weredried (MgSO₄), filtered and the solvent evaporated in vacuo. The crudeproduct was purified by flash chromatography (Biotage Isolera Four; 25 gSfar cartridge) eluting with DCM→95:5 DCM-MeOH to yield((R)-2-methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-proline(1.03 g, 88%) as an orange solid. LCMS (Method A): Rt=2.95 mins;[M−H]−=548.7.

Step 2:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl((R)-2-methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-prolinate

Azithromycin (681 mg, 0.910 mmol), COMU (1.36 g, 3.18 mmol) and DIPEA(0.950 mL, 5.46 mmol) were dissolved in anhydrous DCM (45 mL).((R)-2-Methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-proline(500 mg, 0.910 mmol) was added and the mixture stirred at r.t. for 5days. The mixture was diluted with DCM (25 mL) and the solution washedwith sat. NH₄Cl_((aq)) (2×30 mL). The organic phase was dried (Na₂SO₄),filtered and the solvent evaporated in vacuo. The crude product waspurified by flash chromatography (Biotage Isolera Four; 25 g Sfarcartridge), eluting with 95:5 isohexane-acetone (1% TEA)→60:40isohexane-acetone (1% TEA), to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl((R)-2-methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-prolinate(960 mg, 60%) as an orange solid. LCMS (Method A): Rt=2.06 mins;[M+H]+=1280.9.

Step 3:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl((R)-3-mercapto-2-methylpropanoyl)-L-prolinate

(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl((R)-2-methyl-3-(tris(4-methoxyphenyl)-14-sulfaneyl)propanoyl)-L-prolinate(960 mg, 0.570 mmol) and triethylsilane (0.270 mL, 1.71 mmol) weredissolved in anhydrous DCM (25 mL). Chloroacetic acid (3.95 g, 41.8mmol) was added and the mixture stirred at r.t. for 14 h. The mixturewas diluted with DCM (20 mL), water (25 mL) and triethylamine (5 mL) at0° C. The organic phase was washed with dilute triethylamine in water(25 mL). The organic phase was dried (Na₂SO₄), filtered and the solventevaporated in vacuo. The crude product was purified by flashchromatography (Biotage Isolera Four; 25 g SFar cartridge) eluting with95:5 isohexane-acetone (1% TEA)→60:40 isohexane-acetone (1% TEA), toyield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl((R)-3-mercapto-2-methylpropanoyl)-L-prolinate (31 mg, 6%) as a whitesolid. LCMS (Method A): Rt=2.30 mins; [M+H]+=948.8. ¹H-NMR (400 MHz,CDCl₃) δ 5.06 (d, J=4.8 Hz, 1H), 4.55-4.75 (m, 1H), 4.43 (d, J=7.3 Hz,1H), 3.95-4.36 (m, 3H), 3.66 (t, J=6.6 Hz, 2H), 3.51 (dd, J=15.3, 6.2Hz, 1H), 3.28-3.37 (m, 4H), 3.15-3.28 (m, 1H), 3.02 (t, J=10.1 Hz, 1H),2.53-2.85 (m, 4H), 2.38-2.53 (m, 2H), 2.24-2.38 (m, 9H), 1.40-2.23 (m,13H), 1.01-1.39 (m, 33H), 0.79-0.95 (m, 9H).

Chemical Synthesis Example 7

[(2S,3R,4S,6R)-4-(Dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl](2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoate

Azithromycin (500 mg, 0.668 mmol), COMU (1.00 g, 2.34 mmol) and DIPEA(0.700 mL, 4.02 P2.3 mmol) were dissolved in anhydrous DCM (15 ml).Retinoic acid (all trans) (201 mg, 0.668 mmol) was added and the mixturestirred at 30° for 20 h. The mixture was diluted with DCM (15 ml) andwashed with sat. NH₄Cl_((aq)) (2×15 ml). The organic phase was dried(MgSO₄), filtered and the solvent evaporated in vacuo. The crude productwas purified by flash chromatography (Biotage Isolera Four; 25 g Sfarcartridge), eluting with 95:5 isohexane-acetone (1% TEA)→60:40isohexane-acetone (1% TEA) and further purified by flash chromatography(Biotage Isolera Four; 10 g Sfar cartridge), eluting with 95:5isohexane-acetone (1% TEA)→70:30 isohexane-acetone (1% TEA) to yield[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl](2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoate(25 mg, 4%) as a yellow solid (25 mg, 4%). LCMS (Method A): Rt=2.30mins; [M+H]+=1032.0.

Chemical Synthesis Example 8 Step 1:N-Acetyl-S-(pyridin-2-ylthio)-L-cysteine

2,2′-Dipyridyl disulfide (1.10 g, 4.90 mmol) and N-acetyl-L-cysteine(400 mg, 2.45 mmol) were dissolved in 1:1 water-MeOH (6.8 mL). Thesolution was stirred for 16 h at r.t. The solvent was evaporated invacuo and the crude product purified by flash chromatography elutingwith DCM→75:25 DCM-MeOH to yieldN-acetyl-S-(pyridin-2-ylthio)-L-cysteine (386 mg, 55%) as a yellow oil.LCMS (Method A): R_(t)=1.60 min; [M+H]⁺=273.2.

Step 2:S—(((R)-2-Acetamido-3-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxo-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-3-oxopropyl)thio)-N-acetyl-L-cysteine

To a solution of N-acetyl-S-(pyridin-2-ylthio)-L-cysteine (15.2 mg,0.0600 mmol) in chloroform (2 mL) was added TEA (10 mL, 0.060 mmol) and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylacetyl-L-cysteinate (25.0 mg, 0.030 mmol). The mixture was stirred atr.t. for 1 h. The solvent was evaporated in vacuo and the crude productwas purified by reversed-phase preparative HPLC. The fraction containingproduct was frozen (−78° C.) and the solvent evaporated in vacuo(lyophilisation) to yieldS—(((R)-2-acetamido-3-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-3-oxopropyl)thio)-N-acetyl-L-cysteine(10 mg, 34%) as a white solid. LCMS (Method A): R_(t)=2.20 min;[M+H]⁺=1055.9.

Chemical Synthesis Example 9 Step 1: Ethyl N-acetyl-L-cysteinate

N-Acetyl-L-cysteine (470 mg, 2.88 mmol) was dissolved in ethanol (15 mL)and the reaction mixture degassed with N₂ before cooling to 0° C.Thionyl chloride (210 mL, 2.88 mmol) was added dropwise and the reactionmixture warmed to r.t. and stirred at this temperature for 4 h. Thesolvent was evaporated in vacuo and the mixture diluted with water andEtOAc. The layers were separated, and the aqueous phase extracted withEtOAc (3×10 mL). The combined organics were dried (MgSO₄), filtered andthe solvent evaporated in vacuo. The crude product was purified by flashchromatography (Biotage Isolera Four, 100 g KPSiI column) eluting with75:25 isohexane-EtOAc→15:85 isohexane-EtOAc to yield ethylN-acetyl-L-cysteinate as a pale yellow oil, which crystallised uponextended drying (vac. oven) to give a white solid (180 mg, 33%). ¹H-NMR(400 MHz, CHCl₃): δ 6.47 (d, J=5.7 Hz, 1H), 4.79-4.85 (m, 1H), 4.28-4.16(m, 2H), 2.78-3.22 (m, 2H), 2.03 (s, 3H), 1.36-1.17 (m, 4H).

Step 2: Ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate

2,2′-Dipyridyl disulfide (1.98 g, 4.90 mmol) and ethyl(2R)-2-acetamido-3-sulfanyl-propanoate (0.195 g, 1.02 mmol) weredissolved in a mixture of 1:1 water-MeOH (6.8 mL). The solution wasstirred for 16 h at r.t. The solvent was evaporated in vacuo and thecrude product purified by reversed-phase preparative HPLC. Fractionscontaining product were concentrated under reduced pressure to giveethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate (135 mg, 43%) as acolourless oil. LCMS (Method A): R_(t)=1.96 min; [M+H]+=301.1.

Step 3:(2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylS—(((R)-2-acetamido-3-ethoxy-3-oxopropyl)thio)-N-acetyl-L-cysteinate

To a solution of ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate (15.0mg, 0.050 mmol) in chloroform (2.0 mL) was added TEA (10 mL, 0.060 mmol)and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylacetyl-L-cysteinate (15.0 mg, 0.0168 mmol). The mixture was stirred atr.t. for 28 h. The solvent was evaporated in vacuo to yield the crudeproduct as a yellow oil, which was purified by reversed-phasepreparative HPLC. To each fraction containing desired product was addedDCM (10 mL) and potassium acetate (0.50 g). The layers were separatedand the combined organics dried (MgSO₄), filtered and the solventevaporated in vacuo to yield(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylS—(((R)-2-acetamido-3-ethoxy-3-oxopropyl)thio)-N-acetyl-L-cysteinate(3.5 mg, 19%) as a white solid. LCMS (Method A): R_(t)=1.57 min;[M+H]⁺=1083.9.

Chemical Synthesis Example 10(2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxoactone-1,3-diyl)bis(disulfanediyl))bis(2-acetamidopropanoicacid)

A mixture of(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0600 mmol)were dissolved in THF (15 mL). N-Acetyl-L-cysteine (41.1 mg, 0.250 mmol)was added and the mixture stirred under N₂ at r.t. for 48 h. The solventwas evaporated in vacuo and the crude product purified by reversed-phasepreparative HPLC. Fractions containing desired product were combined andthe solution passed through a catch release cartridge (Biotage Isolute®NH₂; 1 g) washing with MeCN (2 CV). The washings were passed through asecond catch release cartridge (Biotage Isolute® NH₂; 1 g) washing withMeCN (2 CV). Both cartridges were then eluted with 95:5 MeCN—AcOH (2 CV)and the solutions combined, frozen (−78° C.) and the solvent evaporatedin vacuo (lyophilisation) to yield(2′S)-((2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-acetamidopropanoicacid) (14 mg, 15%) as a white solid. LCMS (Method A): R_(t)=1.66 min;[M+H]⁺=1262.2.

Chemical Synthesis Example 11

(2′S)-((2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxoactone-1,3-diyl)bis(disulfanediyl))bis(2-methylpropanoyl))di-L-proline

A mixture of(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol))were dissolved in anhydrous THF (15 mL). Captopril (82 mg, 0.378 mmol)was added and the mixture stirred at r.t. for two weeks. The solvent wasevaporated in vacuo and the crude product purified by reversed-phasepreparative HPLC. Fractions containing desired product were combined andthe solution passed through a catch release cartridge (Biotage IsoluteNH2; 1 g) washing with MeCN (2 CV) and the product eluted with 95:5MeCN—AcOH (2 CV). The eluent was frozen (−78° C.) and the solventevaporated in vacuo (lyophilisation) to yield(2'S)-((2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-methylpropanoyl))di-L-proline(15.0 mg, 17%) as a white solid. LCMS (Method A): R_(t)=1.93 min;[M+H]⁺=1369.8.

Chemical Synthesis Example 12(2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,65)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-(2-mercapto-2-methylpropanamido)propanoicacid)

A mixture of(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,65)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,65)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol)were dissolved in anhydrous THF (15 mL). Bucillamine (70.3 mg, 0.315mmol) was added and the mixture stirred at r.t. for one week. Thesolvent was evaporated in vacuo and the crude product purified byreverse-phase preparative HPLC. Fractions containing desired productwere combined and the solution passed through a catch release cartridge(Biotage Isolute NH2; 1 g) washing with MeCN (2 CV) and the producteluted with 95:5 MeCN—AcOH (2 CV). The solution was froze (−78° C.) andthe solvent evaporated in vacuo (lyophilisation) to yield(2R,2′R)-3,3′-(((R)-8-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-(2-mercapto-2-methylpropanamido)propanoicacid) (5.0 mg, 17%) as a white solid. LCMS (Method F): R_(t)=5.02 min;[(M+H)/2]+=690.7; LCMS (Method A): R_(t)=2.00 min; [M+H]⁺=1379.8.

Chemical Synthesis Example 13(4S,10R)-10-(5-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-5-oxopentyl)-7,7-dimethyl-6-oxo-1,2,8,9-tetrathia-5-azacyclododecane-4-carboxylicacid and(4S,12S)-12-(5-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxo-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-5-oxopentyl)-7,7-dimethyl-6-oxo-1,2,8,9-tetrathia-5-azacyclododecane-4-carboxylicacid

A mixture of(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-2-oxido-1,2-dithiolan-3-yl)pentanoate and(2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol)were dissolved in anhydrous THF (15 mL). Bucillamine (70.3 mg, 0.315mmol) was added and the mixture stirred at r.t. for one week. Thesolvent was evaporated in vacuo and the crude mixture purified byreverse-phase preparative HPLC. Fractions containing desired productwere passed through a catch release cartridge (Biotage Isolute NH2; 1 g)washing with MeCN (2 CV) and the product eluted with 95:5 MeCN—AcOH (2CV). The solution was frozen (−78° C.) and the solvent evaporated invacuo (lyophilisation) to yield the title compounds (7.0 mg, 1.5%) as awhite solid. LCMS (Method E): R_(t)=4.81 min. [(M+H)/2]⁺=580.1; LCMS(Method A) R_(t)=1.90 min. [M+H]⁺=1158.7.

The compounds provided herein (e.g., in Table 1) are prepared accordingto a similar process as provided for any of the Chemical SynthesisExamples, such as, for example, Chemical Synthesis Example 1hereinabove, such as, for example, starting from azithromycin dihydrate.

II. Biological Evaluation Example 1: Rabbit Cornea Homogenate StabilityAssay

Determining Rabbit Cornea Homogenate stability of the test compounds isperformed using HPLC-MS. The assay is performed at two concentrations ofRabbit Cornea Homogenate (0.15 mg/ml and 0.45 mg/ml total protein) sothat any hydrolysis observed can be assigned as esterase dependent ornot.

Rabbit Cornea Homogenisation

Five rabbit corneas (e.g. New Zealand Whites) of approx. 50 mg each aresliced and scraped with a scalpel and tweezers until reduced to small(1-3 mm), thin pieces. These are transferred into a tared vial andaccurately weighed, then diluted with 10 volumes aqueous PBS pH 7.4.

Sample is cooled intermittently on ice and shear homogenized for 3minutes, then centrifuged for 3 min at 3000 rpm. The supernatant ispipetted off into a vial, and total protein concentration determined at280 nm. Sample was stored at −78° C.

Rabbit Cornea Esterase Assay Preparation of Stock Solutions:

10 mM Compound stocks are diluted to 100 μM in a 96 deep-well plate: 10μl of 10 mM Compound stock is added to 990 μl 50 mM HEPES, pH7.5 buffer.Compounds are further diluted to 10 μM: 100 μl of 100 μM compound isadded to 900 μl 50 mM HEPES, pH7.5 buffer. Esterase homogenate isdiluted to 300 ng/μl and 900 ng/μl.

Assay Conditions:

A heater shaker is set to 37° C. Into a suitable 96 well plate (RunPlate), 75 μl of 300 or 900 ng/μl esterase homogenate is pipetted intoeach of the required wells (2 min, 5 min, 10 min, 20 min and 45 min).The plate is sealed and then warmed at 37° C. for 5 min.

Another 96 well PCR plate is put on ice (Kill Plate). To this is added100 μl of MeCN to each well, labelled 0 min 2 min, 5 min, 10 min, 20 minand 45 min. The plate is covered to minimize evaporation.

For the T=0 sample only, to the 100 μl cold MeCN stop solution is added50 μl of 300 or 900 ng/μl esterase homogenate followed by 50 μl of 10 μMcompound solution. For the remaining timepoints, 75 μl of 10 μM compoundsolution is added to the Run Plate starting from T=45 min row and endingwith T=2 min row. At the appropriate time point, 100 p of the assaymixture is added to the matching kill plate well containing 100 μl ofcold MeCN. Samples are analysed as soon as practicable by LCMS (WatersXevo TQ-S or Micromass Ultima).

Parent conjugate and parent concentrations are determined againstappropriate standard response curves and the half-life (T½) of theparent conjugate is calculated using the peak area of the parentconjugate at each time point in the linear region of the log—linearplot.

Example 2: Aqueous Hydrolysis Stability Assay

Determination of aqueous stability of the test compounds is performedusing HPLC-MS. A test compound 10 mM stock solution is prepared in DMSO.10 μl of the DMSO stock solution is dissolved in 990 μl of 50 mM HEPESpH 7.5 buffer or 1:1 (v/v) of Acetonitrile:Water to make a 100 μMsolution. Final DMSO concentration is 1%. The solution is kept at roomtemperature and injected without delay into the LCMS (Waters Xevo TQ-Sor Micromass Ultima). Additional injections are performed at appropriatetime points.

Half-life (T_(1/2)) of the parent conjugate is calculated using the peakarea of the parent conjugate at each time point in the linear region ofthe log—linear plot.

TABLE 2 Hydrolytic % Azithromycin Hydrolytic % keratolytic Compformation at [time] agent formation at [time] 39 C [25 min] — 6, 7,8_(;) and 9 C [60 min] C 5 A [82 min] — A: percent active pharmaceuticalingredient (API) formation <15%; B: percent API formation 15-30%; C:percent API formation >30%.

Example 3: Aqueous Hydrolysis Stability Assay

Compounds with Slow Hydrolysis Rate

Determination of aqueous stability of the test compounds was performedusing UPLC-MS. A test compound 10 mM stock solution was prepared in dryDMSO or DMF. 10 μL of the DMSO or DMF stock solution was dissolved in990 μL of DPBS pH 7.4 buffer to make a 100 μM solution. This solutionwas used “as is” or immediately diluted further with DPBS to 25 μM.Final DMSO concentration was 51%. The solution was immediately placed inan autosampler maintained at 37° C. and injected without delay into theUPLCMS (Waters Xevo TQ-S or G2-XS). Additional injections were performedat appropriate time points. Half-life of the parent compound wasdetermined from the MS response.

Compounds with Fast (<5 Minutes) Hydrolysis Rate

Determination of aqueous stability of the test compounds was performedusing UPLC-MS. A test compound 10 mM stock solution was prepared in dryDMSO or DMF. 50 μL of the DMSO or DMF stock solution was further dilutedwith 150 μL of dry DMSO or DMF (as appropriate) to 2.5 mM. 10 μL of the2.5 mM DMSO or DMF stock solution was dissolved in 990 μL of DPBS pH 7.4buffer to make a 25 μM solution. Final DMSO concentration was 1%. Thesolution was immediately placed in an autosampler maintained at 37° C.and injected without delay into the UPLCMS (Waters Xevo TQ-S or G2-XS).Additional injections were performed at appropriate time points.Half-life of the parent compound was determined from the MS response.

TABLE 3 Hydrolytic % Azithromycin Comp formation at 45 Min Aq T_(1/2)(min) 51 C 53.7 6, 7, 8_(;) and 9 C 29.6 5 C 9.4 44 C <5 45 C <5 46 B51.5 47 C 90.1 33 C 61.5 31 A >120 39 C <5 A: percent activepharmaceutical ingredient (API) formation <15%; B: percent API formation15-30%; C: percent API formation >30%.

Example 4: Mouse Model of Experimental Dry Eye Disease

Female C57BL/6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8 weeksold) are commercially obtained. Experimental dry eye is induced asdescribed by Niederkorn, et al. (J. Immunol. 2006, 176:3950-3957) andDursun et al. (Invest. Ophthalmol. Vis. Sci. 2002, 43:632-638). Inbrief, mice are exposed to desiccating stress in perforated cages withconstant airflow from fans positioned on both sides and room humiditymaintained at 30% to 35%. Injection of scopolamine hydrobromide (0.5mg/0.2 mL; Sigma-Aldrich, St. Louis, Mo.) is administeredsubcutaneously, three times a day (8:00 AM, 12:00 noon, and 5:00 PM), onalternating hind-flanks to augment disease. Mice are exposed todesiccating stress for 3 weeks. Untreated control mice are maintained ina nonstressed environment at 50% to 75% relative humidity withoutexposure to forced air. Test animals are exposed to test compound andsubsequently tear samples are obtained to determine stability of testcompounds, and tissue samples are taken to determine presence ofpro-inflammatory biomarkers.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Solution forTopical Ophthalmic Use

The active ingredient is a compound of Table 1, or a pharmaceuticallyacceptable salt thereof, and is formulated as a solution with aconcentration of from 0.1-1.5% w/v.

1. (canceled)
 2. A compound having a structure represented by Formula(Ia):

or a pharmaceutically acceptable salt or solvate thereof, wherein, L isbond, —(C═O)(OCR⁸R⁹)_(z)—, or —(C═O)(CR⁸R⁹)_(z)O—; each R⁸ and R⁹ isindependently H, halogen, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₃-C₅-cycloalkyl, or R⁸ and R⁹ are taken together with the atoms towhich they are attached to form a C₃-C₅-cycloalkyl; z is 1-6; X isabsent or —O—; and R is substituted alkyl, the substituted alkyl beingsubstituted with one or more alkyl substituent, at least one alkylsubstituent being independently selected from the group consisting of—SH, substituted or unsubstituted cycloalkyl, and substituted saturatedheterocyclyl.
 3. The compound of claim 1, wherein R is alkyl substitutedwith —SH.
 4. The compound of claim 1, wherein R alkyl substituted withsubstituted or unsubstituted cycloalkyl.
 5. The compound of claim 4,wherein R alkyl substituted with substituted unsaturated cycloalkyl. 6.The compound of claim 1, wherein R is alkyl substituted with substitutedsaturated heterocyclyl.
 7. The compound of claim 6, wherein thesubstituted saturated heterocyclyl is dithiolanyl oxide.
 8. The compoundof claim 1, wherein X is absent.
 9. The compound of claim 1, wherein Lis a bond.
 10. The compound of claim 1, wherein L is—(C═O)(OCR⁸R⁹)_(z)O—.
 11. The compound of claim 10, wherein each R⁸ andR⁹ is H.
 12. The compound of claim 10, wherein z is 1-4.
 13. Thecompound of claim 1, wherein X is absent and L is a bond.
 14. Thecompound of claim 1, wherein X is absent and L is —(C═O)(OCR⁸R⁹)_(z)O—.15. The compound of claim 1, wherein R is alkyl substituted with —SH, Xis absent, and L is a bond.
 16. The compound of claim 1, wherein R isalkyl substituted with dithiolanyl oxide, X is absent, and L is a bond.17. The compound of claim 1, wherein R is alkyl substituted withdithiolanyl oxide, X is absent, and L is —(C═O)(OCR⁸R⁹)_(z)O—.
 18. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 19. The pharmaceuticalcomposition of claim 18, wherein the pharmaceutical composition issuitable for topical ophthalmic administration.
 20. A method of treatinga dermal or an ocular disease or disorder in an individual, comprisingadministering to the individual a compound of claim
 1. 21. The method ofclaim 20, wherein the dermal or the ocular disease or disorder isassociated with keratosis, microbial infiltration, microbial infection,inflammation, or any combination thereof.